Objective: To compare the effectiveness of two oral analgesic regimens in first trimester medical abortion. Methods: We randomly assigned 250 women undergoing first trimester abortion with mifepristone and misoprostol at three clinics to two ibuprofen regimens: therapeutic (800 mg every 4-6 hours as needed for pain), or prophylactic (800 mg starting 1 hour before the misoprostol dose, then every 4-6 hours for 48 hours regardless of pain, then as needed). We asked each subject to record her maximum pain on a scale of 0-10 daily thereafter. Results: Of subjects assigned to the prophylactic and therapeutic regimens, 111/123 (89%) and 117/127 (91%), respectively, provided follow-up data. More than 80% of the participants in each group complied with their assigned treatment. Participants in the prophylactic group used substantially more ibuprofen than those in the therapeutic group (median of 9 and 4 tablets, respectively). The mean maximum pain score was 7.1 in the prophylactic group and 7.3 in the therapeutic group (estimated difference -0.17; 95% confidence limits -0.78, 0.44). Duration of pain, verbal pain ratings reported at follow-up, and use of other analgesics did not differ significantly by group (all p>0.05). No significant benefit of the prophylactic regimen was apparent in any population subgroup. Abortion failure and ibuprofen side effects in the two groups were similar. Conclusion: We found no evidence that prophylactic, “around-the-clock” administration of ibuprofen reduces pain severity or duration in first trimester medical abortion. The average pain severity experienced by women using both regimens was high.