Sex differences in steroid metabolism have been clearly demonstrated in animal studies, but few studies have addressed this question in the human. Our preliminary studies suggested human sex differences in both cortisol production and metabolism. We therefore looked in more detail at indices of cortisol metabolism derived from 24 hour urinary steroid profiles in a group of 20 men and 20 women who were age-matched, drug-free and had no endocrine disorder. Steroid analysis was by high resolution gas chromatography. Men excreted more total cortisol metabolites (7620 +/- 620 v 4750 +/- 380 micrograms/24 h, p < 0.001), 11-oxo metabolites of cortisol (11-oxo FM, 4320 +/- 400 v 2890 +/- 250 micrograms/24 h, p < 0.001) and 11 beta-hydroxy metabolites of cortisol (11-OH FM, 3290 +/- 240 v 1860 +/- 140 micrograms/24 h, p < 0.001). These differences remained significant when corrected for body surface area. The ratio of 11-oxo FM/11-OH FM, an index of 11 beta-hydroxysteroid dehydrogenase (11-HSD) activity, was higher in women (1.57 +/- 0.07 v 1.31 +/- 0.06, p < 0.01). The ratios of 5 alpha/5 beta and 20-oxo/20-OH metabolites of cortisol were both higher in men (1.07 +/- 0.15 v 0.58 +/- 0.04, p < 0.01, and 2.78 +/- 0.06 v 2.27 +/- 0.11, p < 0.01), while the ratio of 20 alpha/20 beta metabolites of cortisol was higher in women (1.79 +/- 0.13 v 1.32 +/- 0.06, p < 0.01). We conclude that there are considerable sex differences in both the production and metabolism of cortisol in healthy men and women. In particular, the data are consistent with a sex difference in 11-HSD activity, with relatively greater conversion of cortisol to cortisone in women.