The relative effects of rifampin and rifabutin (a related rifamycin) on the pharmacokinetics and pharmacodynamics of ethinyl estradiol (EE) and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 mcg EE and 1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. Findings showed that rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC (0-24)] of EE and the mean AUC (0-24) of norethindrone. Rifabutin significantly decreased the mean AUC (0-24) of EE and the mean AUC (0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC (0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. This study suggests that rifampin (600 mg daily) was a more important inducer of EE and norethindrone clearance than rifabutin, but none of these agents were able to reverse the suppression of ovulation done by oral contraceptives.