An open-label, nonrandomized, parallel, controlled study compared the efficacy, safety, and cycle control of a new monthly injectable contraceptive containing 25 mg of medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) with that of a norethindrone 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic oral contraceptive (Ortho-Novum 7/7/7). At study enrollment, women chose either the injections or the oral contraceptive. A higher proportion of women in the NET/EE group (65.1%) than in the MPA/E2C group (48.7%) had used hormonal contraception during the month before the study (p < 0.01). Overall, 55.5% (434/782) of MPA/E2C users and 67.6% (217/321) of NET/EE users completed the 60-week trial. One-year contraceptive efficacy (13 cycles of 28 days) for MPA/E2C and NET/EE was based on 8008 and 3434 woman-cycles of use, respectively. During the first year, one pregnancy occurred in an NET/EE user for a life table rate of 0.3; no pregnancies occurred in users of MPA/E2C. One additional pregnancy in the NET/EE group occurred during the 15th treatment cycle. After the first treatment cycle, women in both groups experienced regular menses, with an average cycle length of 28 days in MPA/E2C users and 27 days in NET/EE users. Although MPA/E2C users were more likely to experience bleeding irregularities, only 2.5% (19/775) cited metrorrhagia as a reason for discontinuing treatment. The adverse events reported in both treatment groups are consistent with those expected with the use of combined hormonal contraceptives. Overall, the results of this first Phase III US clinical trial of MPA/E2C confirm this method's high contraceptive efficacy and safety, as shown in previous studies by the World Health Organization. These results suggest that a monthly combination injectable would represent a welcome new contraceptive option for women in the US.