The high ratio of women with systemic lupus erythematosus (SLE) has remained unexplained, despite the recent description of metabolic abnormalities of estrogen and androgen metabolism. Alterations of steroid metabolism in patients with SLE could be important in the pathogenesis of this disease, since it has been reported that gonadal steroids modulate the immune system. Moreover, research with inbred lupus mice has shown that estrogens have adverse effects on the disease in both sexes, whereas androgen therapy or oophorectomy is protective in females. Recently, the finding of elevated testosterone oxidation at C-17 in females with SLE suggested that plasma androgen levels in males and females with SLE should be examined more closely. We studied the varying degrees of clinical activity, with regard to plasma levels of 4 significant androgens: testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate in a series of 5 male and 42 female SLE patients. Decreased levels of all androgens were observed in women with SLE. The lowest levels of plasma androgens were found in female patients who had active disease, as determined by laboratory and clinical assessment. These data support the fact that specific abnormalities of androgen metabolism in the female are associated with SLE, and may contribute in some way to morbidity and mortality. More importantly, these data may have implications for future therapeutic regimens based on male hormone replacement.