The sera of 21 adult patients with acute leukemia were studied for the presence of antibody reacting with surface antigens of autologous leukemia cells. Sequential serum samples were obtained from patients and were tested on cryopreserved leukemia cells in immune adherence assays. Three patients showed autologous serum reactivity and the serum of one of them was analyzed in detail. This antibody reacted with autologous acute lymphocytic leukemia cells but not with autologous cells obtained from peripheral blood, bone marrow, or spleen during clinical remission. In absorption tests, the antigen could not be detected on normal autologous or allogeneic blood lymphocytes, lymphoblastoid lines of T- or B-cell origin, or cells infected with simian sarcoma virus, baboon C-type virus, or Mason-Pfizer virus. Leukemia cells from two other patients with acute lymphocytic leukemia and one patient with acute nonlymphocytic leukemia absorbed specific reactivity. These studies indicate that certain acute leukemia cells express a common antigen that elicits a humoral immune response in the autologous host.