diff --git a/protected/java/src/org/broadinstitute/sting/gatk/walkers/compression/reducereads/ReduceReads.java b/protected/java/src/org/broadinstitute/sting/gatk/walkers/compression/reducereads/ReduceReads.java
index 71910e566..eb55701ae 100644
--- a/protected/java/src/org/broadinstitute/sting/gatk/walkers/compression/reducereads/ReduceReads.java
+++ b/protected/java/src/org/broadinstitute/sting/gatk/walkers/compression/reducereads/ReduceReads.java
@@ -64,6 +64,7 @@ import org.broadinstitute.sting.gatk.io.StingSAMFileWriter;
 import org.broadinstitute.sting.gatk.refdata.RefMetaDataTracker;
 import org.broadinstitute.sting.gatk.walkers.*;
 import org.broadinstitute.sting.utils.GenomeLoc;
+import org.broadinstitute.sting.utils.SampleUtils;
 import org.broadinstitute.sting.utils.Utils;
 import org.broadinstitute.sting.utils.clipping.ReadClipper;
 import org.broadinstitute.sting.utils.exceptions.ReviewedStingException;
@@ -236,6 +237,15 @@ public class ReduceReads extends ReadWalker<ObjectArrayList<GATKSAMRecord>, Redu
     @Argument(fullName = "downsample_coverage", shortName = "ds", doc = "", required = false)
     public int downsampleCoverage = 250;
 
+    /**
+     * Generally, this tool is not meant to be run for more than 1 sample at a time.  The one valid exception
+     * brought to our attention by colleagues is the specific case of tumor/normal pairs in cancer analysis.
+     * To prevent users from unintentionally running the tool in a less than ideal manner, we require them
+     * to explicitly enable multi-sample analysis with this argument.
+     */
+    @Argument(fullName = "cancer_mode", shortName = "cancer_mode", doc = "enable multi-samples reduction for cancer analysis", required = false)
+    public boolean ALLOW_MULTIPLE_SAMPLES = false;
+
     @Hidden
     @Argument(fullName = "nwayout", shortName = "nw", doc = "", required = false)
     public boolean nwayout = false;
@@ -294,6 +304,9 @@ public class ReduceReads extends ReadWalker<ObjectArrayList<GATKSAMRecord>, Redu
         if ( minAltProportionToTriggerVariant < 0.0 || minAltProportionToTriggerVariant > 1.0 )
             throw new UserException.BadArgumentValue("--minimum_alt_proportion_to_trigger_variant", "must be a value between 0 and 1 (inclusive)");
 
+        if ( SampleUtils.getSAMFileSamples(getToolkit().getSAMFileHeader()).size() > 1 && !ALLOW_MULTIPLE_SAMPLES )
+            throw new UserException.BadInput("Reduce Reads is not meant to be run for more than 1 sample at a time except for the specific case of tumor/normal pairs in cancer analysis");
+
         if ( known.isEmpty() )
             knownSnpPositions = null;
         else
diff --git a/protected/java/src/org/broadinstitute/sting/gatk/walkers/compression/reducereads/SlidingWindow.java b/protected/java/src/org/broadinstitute/sting/gatk/walkers/compression/reducereads/SlidingWindow.java
index d3ca037be..8843d6270 100644
--- a/protected/java/src/org/broadinstitute/sting/gatk/walkers/compression/reducereads/SlidingWindow.java
+++ b/protected/java/src/org/broadinstitute/sting/gatk/walkers/compression/reducereads/SlidingWindow.java
@@ -877,6 +877,10 @@ public class SlidingWindow {
                     final int start = region.getStart() - windowHeaderStart;
                     int stop = region.getStop() - windowHeaderStart;
 
+                    // make sure the bitset is complete given the region (it might not be in multi-sample mode)
+                    if ( region.getStop() > markedSites.getStartLocation() + markedSites.getVariantSiteBitSet().length )
+                        markSites(region.getStop());
+
                     CloseVariantRegionResult closeVariantRegionResult = closeVariantRegion(start, stop, knownSnpPositions);
                     allReads.addAll(closeVariantRegionResult.reads);
 
diff --git a/protected/java/test/org/broadinstitute/sting/gatk/walkers/compression/reducereads/ReduceReadsIntegrationTest.java b/protected/java/test/org/broadinstitute/sting/gatk/walkers/compression/reducereads/ReduceReadsIntegrationTest.java
index 15b54dbd1..405e616f1 100644
--- a/protected/java/test/org/broadinstitute/sting/gatk/walkers/compression/reducereads/ReduceReadsIntegrationTest.java
+++ b/protected/java/test/org/broadinstitute/sting/gatk/walkers/compression/reducereads/ReduceReadsIntegrationTest.java
@@ -53,6 +53,7 @@ import org.testng.annotations.Test;
 
 import java.io.File;
 import java.util.Arrays;
+import java.util.Collections;
 import java.util.List;
 
 public class ReduceReadsIntegrationTest extends WalkerTest {
@@ -221,13 +222,13 @@ public class ReduceReadsIntegrationTest extends WalkerTest {
 
     @Test(enabled = true)
     public void testCoReduction() {
-        String base = String.format("-T ReduceReads %s -npt -R %s -I %s -I %s", COREDUCTION_L, REF, COREDUCTION_BAM_A, COREDUCTION_BAM_B) + " -o %s ";
+        String base = String.format("-T ReduceReads %s --cancer_mode -npt -R %s -I %s -I %s", COREDUCTION_L, REF, COREDUCTION_BAM_A, COREDUCTION_BAM_B) + " -o %s ";
         executeTest("testCoReduction", new WalkerTestSpec(base, Arrays.asList("bam"), Arrays.asList("5f4d2c1d9c010dfd6865aeba7d0336fe")), COREDUCTION_QUALS_TEST_MD5);
     }
 
     @Test(enabled = true)
     public void testCoReductionWithKnowns() {
-        String base = String.format("-T ReduceReads %s -npt -R %s -I %s -I %s -known %s", COREDUCTION_L, REF, COREDUCTION_BAM_A, COREDUCTION_BAM_B, DBSNP) + " -o %s ";
+        String base = String.format("-T ReduceReads %s --cancer_mode -npt -R %s -I %s -I %s -known %s", COREDUCTION_L, REF, COREDUCTION_BAM_A, COREDUCTION_BAM_B, DBSNP) + " -o %s ";
         executeTest("testCoReductionWithKnowns", new WalkerTestSpec(base, Arrays.asList("bam"), Arrays.asList("ca48dd972bf57595c691972c0f887cb4")), COREDUCTION_QUALS_TEST_MD5);
     }
 
@@ -281,5 +282,24 @@ public class ReduceReadsIntegrationTest extends WalkerTest {
                 " -o %s  --downsample_coverage 250 -dcov 50  ";
         executeTest("testPairedReadsInVariantRegion", new WalkerTestSpec(base, Arrays.asList("bam"), Arrays.asList("7e7b358443827ca239db3b98f299aec6")), "2af063d1bd3c322b03405dbb3ecf59a9");
     }
+
+    /**
+     * Confirm that this bam does not fail when multi-sample mode is enabled.  The provided example is tricky and used to cause
+     * us to exception out in the code.
+     */
+    @Test(enabled = true)
+    public void testMultiSampleDoesNotFailWithFlag() {
+        String cmd = "-T ReduceReads --cancer_mode -npt -R " + b37KGReference + " -I " + privateTestDir + "rr_multisample.bam -o /dev/null";
+        executeTestWithoutAdditionalRRTests("testMultiSampleDoesNotFailWithFlag", new WalkerTestSpec(cmd, 0, Collections.<String>emptyList()));
+    }
+
+    /**
+     * Confirm that this bam fails when multi-sample mode is not enabled
+     */
+    @Test(enabled = true)
+    public void testMultiSampleFailsWithoutFlag() {
+        String cmd = "-T ReduceReads -npt -R " + b37KGReference + " -I " + privateTestDir + "rr_multisample.bam -o /dev/null";
+        executeTestWithoutAdditionalRRTests("testMultiSampleDoesNotFailWithFlag", new WalkerTestSpec(cmd, 0, UserException.BadInput.class));
+    }
 }