Complete deficiency of the complement C4A isotype is a known genetic risk factor for systemic lupus erythematosus (SLE). The disease phenotype of C4A-deficient patients has never been defined. Among 200 patients with SLE from five centers, 18 (9%) with C4A deficiency were identified. These individuals were compared to those who were C4A replete with regard to a series of clinical and serologic features. The only significant differences between the two groups were in the presence of renal disease (C4A deficient, 11%; C4A replete, 46%; P < 0.006) and a decrease in the serum concentrations of C3 (C4A deficient, 11%; C4A replete, 35%; P < 0.04). There was also a trend for the C4A-deficient individuals to have milder disease. In light of the tendency for C4A-deficient individuals to have lower serum concentrations of C4, it is important that such patients not be subjected to overly aggressive efforts to "normalize" their C4 levels.