Histiocytic hyperplasia with hemophagocytosis (HHH) is a relatively rare condition that has often been mistaken for a neoplastic disorder, but which most frequently represents a secondary reactive phenomenon whose associated risk factors have not yet been clearly defined. Histologic sections of hematopoietic organs (bone marrow, lymph nodes, and spleen) from 230 consecutive adults autopsies were reviewed to identify cases of HHH and to correlate them with clinical and autopsy findings. Moderate to severe HHH was present in the bone marrow in 102 and 230 cases, in the lymph nodes in 79 of 191 cases, and in the spleens of 16 of 209 cases. Recent blood transfusions, bacterial sepsis, major surgery, underlying disseminated malignancy, Candida sepsis, and viral infection were studied as potential risk factors. Both crude and adjusted analyses indicated a strong association between recent blood transfusions and the development of HHH in the bone marrow (P less than .0001). There was a marked dose-response relationship between number of units and the risk of HHH, with an adjusted risk ratio of 59.9 for five or more units compared with no transfusions. Bacterial sepsis was also associated with a significantly increased risk of HHH in the bone marrow in both the crude and adjusted analyses (adjusted risk ratio, 4.10; P = .0002). Major surgery and viral infection were only marginally associated with an increased risk for HHH (P = .03 and P = 0.06, respectively), and underlying disseminated malignancy and Candida sepsis did not appear to contribute any risk. Analyses for HHH in lymph nodes and spleen were similar to analysis for the bone marrow, but were somewhat less marked. The results of this study suggest that reactive HHH in hematopoietic organs may be far more common than has previously been acknowledged, and is most often multifactorial rather than related to a single underlying condition, with transfusions and bacterial sepsis constituting the most significant risk factors. Therefore, reactive HHH may represent a frequent secondary phenomenon in critically ill patients undergoing transfusions and should not be mistaken for an ominous sign or for the development of a superimposed malignancy.