Hepatitis B virus (HBV) infection and replication have been linked to the development of hepatocellular carcinoma. Bone marrow-derived cells, as well as mesenchymal and epithelial cells, were recently shown to support HBV replication. We hypothesize that the mechanism that links HBV infection and liver tumors might also promote tumor development in tissues permissive for HBV replication. Between 1980 and 1993 we retrospectively identified 22 patients who were hepatitis B surface antigen (HBsAg) carriers and had extra-hepatic malignancies. These patients had 25 tumors, of which 22 were bone marrow derived. HBsAg was detected by immunohistochemistry in bone marrow cells of leukemia patient and of 3 of 10 lymphoma patients. In addition, in 4 of 10 patients with lymphoma, including 2 patients in which HBsAg stained bone marrow cells, HBsAg was also detected in the endothelial cells of blood vessels of the tumor tissue. These results suggest that the identification of an HBV gene product in endothelial cells might point to a role of HBV infection in the development of certain hematopoietic tumors, possibly through activation of cytokines or growth factors, which may eventually lead to bone marrow cell proliferation.