Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disease characterized by abnormal activation of T-lymphocytes and macrophages. The diagnosis of HLH can be established if there is a family history of HLH, or evidence of genetic defects, or if 5 of 8 clinicopathologic criteria are fulfilled. This case-control study aimed to examine the extent of hemophagocytosis on the bone marrow examination of patients fulfilling diagnostic criteria for HLH. Hemophagocytosis in 6 bone marrow aspirates from 3 HLH patients was compared with 20 random control bone marrows. Macrophages with hemophagocytosis were counted using a Miller ocular disc in fields corresponding to 9,000 nucleated cells. Mean hemophagocytosis count in the HLH cases was estimated at 0.082% (range 0-0.31%), whereas in the controls it was 0.009% (range 0-0.04%). The sensitivity of hemophagocytosis was 83% with a specificity of only 60%. This demonstrates that rare hemophagocytosis can be seen in bone marrow aspirates from patients without a clinical diagnosis of HLH. It also shows that hemophagocytosis has too low a specificity to be a screening test for HLH. While the hemophagocytosis counts are significantly higher in HLH cases than in controls, overlap of the counts precludes using hemophagocytosis as a reliable indicator of HLH. A rise in the hemophagocytosis count threshold of 0.05-0.13% would increase the specificity to 100%. We suggest that the diagnostic scheme for HLH needs revision, and can be improved by addressing minimum hemophagocytosis count threshold.