Our study was undertaken to determine the influence of sex and the use of oral contraceptive steroids on antipyrine clearance and metabolite formation. Our subjects were eight men (M), eight women (F), and eight women who had been using oral contraceptive steroids (OC) for at least 6 mo; all were healthy. The groups were matched for age and smoking and drinking habits. Antipyrine elimination half-life (t1/2) was longer in the OC than in the F group (12.9 +/- 2.0 and 9.7 +/- 1.7 hr) and clearance was lower (2.0 +/- 0.1 and 2.8 +/- 0.5 l/hr), while volume of distribution (Vd) was essentially the same (37.1 +/- 5.7 and 38.5 +/- 4.6 l). The M group had longer t1/2s than the F (11.8 +/- 1.2 and 9.7 +/- 1.7 hr) and greater Vds (47.1 +/- 5.4 and 38.5 +/- 4.6 l), but clearance values were the same (2.8 +/- 0.5 and 2.8 +/- 0.5 l/hr) in the two groups. Compared to the F, the three metabolic pathways of antipyrine appeared to be inhibited in the OC group. Partial clearances for production for the F and OC groups were (l/hr); norantipyrine (NORA) 0.70 +/- 0.13 and 0.42 +/- 0.12, 4-hydroxyantipyrine (OHA) 1.19 +/- 0.37 and 0.83 +/- 0.25, and 3-hydroxymethylantipyrine (HMA) 0.45 +/- 0.10 and 0.33 +/- 0.09. Partial clearance for production in the F group was higher than in the M for OHA (1.19 +/- 0.37 and 0.78 +/- 0.15 l/hr) and NORA (0.07 +/- 0.13 and 0.56 +/- 0.13 l/hr), but not for HMA (0.45 +/- 0.10 and 0.40 +/- 0.05 l/hr). In the F group, total metabolite recovery was higher than the M. We conclude that sex and OC steroids have differential effect on the several metabolic pathways of antipyrine.