Systemic lupus erythematosus (SLE) is one of many chronic diseases with a predilection for the human female. The reasons for the high female to male (9:1) incidence remain unknown. The total extent of hydroxylation estradiol at either C-16 to more estrogenic metabolites or at C-2 to the catechol estrogens was determined by a radiometric method in the human. Comparing 23 SLE patients to 44 normal controls, an increase in the extent of hydroxylation toward the 16α-metabolites was found in SLE (SLE 15.2 ± 4.3±, range 8.8–30±; normal 9.1 ± 2.3±, range 5.3–14.4%; P < 0.001). Increased 16α-hydroxylation was found in both males (SLE 13.2 ± 3.0%, normal 8.3 ± 2.1%) and females (SLE 15.7 ± 5%, normal 9.9 ± 2.2%) with disease when compared to normal subjects. In addition, studies of several other chronic diseases by the same method did not indicate a similar alteration in 16-hydroxylation. No change in hydroxylation at C-2 was found in male patients, but a decrease was found in female patients. These data suggest that increased hydroxylation of estradiol at C-16 occurs in SLE. The 16ametabolites have been shown to be potent estrogens, and these data might give some insight into the pathogenesis of the disease. (J.Clin Endocrinol Metab53: 174, 1981)