diff --git a/intrahost.py b/intrahost.py
index 917cd019c..1f073c329 100755
--- a/intrahost.py
+++ b/intrahost.py
@@ -133,6 +133,14 @@ def vphaser_one_sample(inBam, inConsFasta, outTab, vphaserNumThreads=None,
         samtoolsTool.index(bam_to_process)
         os.unlink(leading_or_trailing_indels_removed)
 
+    # For low-quality data, the process of removing doubly-mapped reads
+    # can remove all reads. In such cases, stub out an empty vphaser output
+    # file to allow the pipeline to continue
+    if samtoolsTool.count(bam_to_process) == 0:
+        log.warning("The bam file %s has 0 reads after removing doubly-mapped reads. Writing blank V-Phaser output.", bam_to_process)
+        util.file.touch(outTab)
+        return None
+
     variantIter = Vphaser2Tool().iterate(bam_to_process, vphaserNumThreads)
     filteredIter = filter_strand_bias(variantIter, minReadsEach, maxBias)
 
diff --git a/test/input/TestPerSample/in.oneunmapped.bam b/test/input/TestPerSample/in.oneunmapped.bam
new file mode 100644
index 000000000..5fca12fba
Binary files /dev/null and b/test/input/TestPerSample/in.oneunmapped.bam differ
diff --git a/test/integration/test_intrahost.py b/test/integration/test_intrahost.py
index a97691781..bb7bbc981 100644
--- a/test/integration/test_intrahost.py
+++ b/test/integration/test_intrahost.py
@@ -16,7 +16,7 @@
 import test
 import tools
 
-@unittest.skipIf(tools.is_osx(), "vphaser2 osx binary from bioconda has issues")
+#@unittest.skipIf(tools.is_osx(), "vphaser2 osx binary from bioconda has issues")
 class TestPerSample(test.TestCaseWithTmp):
     ''' This tests step 1 of the iSNV calling process
         (intrahost.vphaser_one_sample), which runs V-Phaser2 on
@@ -43,6 +43,21 @@ def test_vphaser_one_sample_indels(self):
         expected = os.path.join(myInputDir, 'vphaser_one_sample_indels_expected.txt')
         self.assertEqualContents(outTab, expected)
 
+    def test_vphaser_one_sample_one_mate_unpaired(self):
+        # Files here were created as follows:
+        # ref.indels.fasta is Seed-stock-137_S2_L001_001.fasta
+        # in.oneunmapped.bam was created from in.indels.bam, with flag 0->89, 16->73:
+        # When removing doubly mapped reads, doing so can result in all reads
+        # being removed in the case of low-quality runs with few reads
+        # This tests that when v-phaser2 input is empty, a blank
+        # file is created as output.
+        myInputDir = util.file.get_test_input_path(self)
+        inBam = os.path.join(myInputDir, 'in.oneunmapped.bam')
+        refFasta = os.path.join(myInputDir, 'ref.indels.fasta')
+        outTab = util.file.mkstempfname('.txt')
+        intrahost.vphaser_one_sample(inBam, refFasta, outTab, vphaserNumThreads=4, minReadsEach=0, removeDoublyMappedReads=True)
+        assert os.path.getsize(outTab) == 0
+
     def test_vphaser_one_sample_2libs(self):
         # in.2libs.bam was created by "manually" editing in.bam and moving about
         # 1/3 of the reads to ReadGroup2.