Leptin promotes the growth and viability of hematopoietic cells, and it also stimulates microvessel formation, indicating a role for leptin in angiogenesis. Acute myelocytic leukemia (AML) remains a disease with poor prognosis. Similar to solid tumors, it probably requires angiogenesis to ensure adequate supplies of nutrients. We studied rats with transplanted AML to test if a neutralizing anti-leptin receptor monoclonal antibody (mAb) (anti-OB-R) could inhibit leukemogenesis. At 4 weeks after transplantation, the bone marrow contained about 80% leukemic cells as assayed with a specific mAb and flow cytometry. Microscopic examination of bone marrow sections stained with an anti-von Willebrand mAb revealed a marked increase in microvessel density in the leukemic rats compared with controls. Treatment with anti-OB-R for 3 weeks more than halved the content of bone marrow leukemic cells with a concomitant, substantial decrease in angiogenesis. A parallel experiment using an irrelevant anticasein mAb showed no effect on either leukemic cell growth or angiogenesis. We could not detect surface expression of the leptin receptor on the leukemic cells, but on mononuclear cells from healthy rats. The anti-OB-R did not affect in vitro proliferation of leukemic cells whereas proliferation of the mononuclear cells was markedly impaired. The anti-OB-R had no effect on either leukemic cell growth or angiogenesis in leukemic fa/fa rats with a mutated leptin receptor. We conclude that leptin stimulates leukemic cell growth in vivo by promoting angiogenesis. Inhibition of binding of leptin to its receptor might be a new adjunct therapy in AML.