Formation of an aberrant, chimeric Bcr-Abl protein is the hallmark of Philadelphia (Ph) chromosome-positive leukemias. The Bcr-Abl protein, as well as its normal cellular counterparts--Abl and Bcr--are intracellular molecules with postulated roles in a variety of critical biologic functions. In this study, we demonstrate the existence of autoantibodies against these proteins. Plasma from 18 of 31 individuals (58%), including 14 of 20 Ph-positive CML patients (70%), two of four normal volunteers (50%), and two of seven patients with Ph-negative leukemia (29%) recognized p210Bcr-Abl when used in immunoprecipitation followed by immunoblotting experiments. In all 18 patients, plasma was able to recognize baculovirus-expressed Abl protein; in four patients, recognition of baculovirus-expressed Bcr protein was also demonstrated. These observations suggest that a humoral immune response to p210Bcr-Abl is discernible in both Ph-positive and -negative leukemias and in healthy individuals, and is most likely due to autoantibodies which recognize normal Abl and, to a lesser extent, normal Bcr proteins.