Using RNA hybridization techniques, we examined the expression of proto-oncogenes associated with lymphocyte activation in vitro in patients with systemic lupus erythematosus and other autoimmune diseases. T and B lymphocytes from these patients were found to have significantly increased expression of c-myc, c-myb, and c-raf RNA when compared with those of normal individuals. Among the mononuclear cell subpopulations, B lymphocytes expressed higher levels of RNA for these proto-oncogenes compared with the T lymphocytes. Since prompt expression of these and other proto-oncogenes occurs in fibroblasts and lymphocytes following mitogenic stimulation, we propose that the present findings reflect the pathologically activated state of various lymphocytic subpopulations which is observed in systemic lupus erythematosus and in other autoimmune diseases. Endogenous and exogenous factors which lead to the expression of autoimmunity might share the induction of proto-oncogene expression as a common pathogenetic step.