Doxycycline and other antibiotics have been implicated in oral contraceptive (OC) failure, but information is sparse and studies of a doxycycline-OC interaction are nonexistent. Because an interaction between doxycycline and OCs, especially those containing low-dose estrogen, could result in an unplanned and unwanted pregnancy, a controlled clinical trial of the effects of doxycycline on OC hormone concentrations was performed. Twenty-four women aged 18-35 years were recruited as volunteers from among the patients seen in a University-based family planning clinic. While they were on a steady dose of the OC Ortho-Novum 1/35, serum concentrations of ethinyl estradiol, norethindrone, and endogenous progesterone were measured on days 18, 19, and 20 of the menstrual cycle (control phase). These measurements were repeated on days 18, 19, and 20 of the following menstrual cycle while the patient was taking doxycycline, 100 mg twice daily (treatment phase). No statistically significant differences in serum levels of ethinyl estradiol, norethindrone, or endogenous progesterone were seen between the control and treatment phases. However, there was large inter-patient and intra-patient variability in ethinyl estradiol and norethindrone levels. No elevations of endogenous progesterone occurred to suggest ovulation during antibiotic administration in either phase. It is not known what effects longer or earlier administration of doxycycline during the OC cycle would have on serum hormone concentrations or ovulation. Pregnancies attributed to failure of OCs because of tetracycline use could in fact be due to other causes or could represent a true interaction that only manifests itself in a small proportion of women at risk.