Various genetic studies indicate that development of systemic lupus erythematosus (SLE) is regulated by the mode of multifactorial inheritance, i.e., by the overall effect of polygenes and environmental factors. To elucidate some variant genes involved in the polygenic system responsible for onset of SLE, we resolved and measured the protein components of lymphocytes and sera from inactive-SLE patients, their relatives, and normal controls, using two-dimensional gel electrophoresis. Intercomparison of polypeptide patterns between patients and controls revealed three major variations, two detected in lymphocytes and one in sera. These variations were present in 66-82% of the patients, in 20-36% of the control group, and in 41-64% of the relatives. In addition, nearly half of SLE patients, but only one of 19 normal controls, possessed all three SLE-associated traits, suggesting that these variant proteins may reflect in part the genetic factors contributing to development of SLE.