Objectives: To determine whether prophylactic administration of ibuprofen and metoclopramide or tramadol alone provides superior pain relief compared to analgesia when pain begins with mifepristone and misoprostol medical abortion through 63 days gestation. Methods: We conducted a multi-center randomized, placebo-controlled trial in Nepal, South Africa and Vietnam. Participants were randomized 1:1:1 to: (1) ibuprofen 400 mg and metoclopramide 10 mg ; (2) tramadol 50 mg and a placebo; or (3) two placebo, taken immediately before misoprostol and repeated four hours later. All women had supplementary analgesia to use as needed. Our primary outcome was maximum pain within 8 h of misoprostol administration. Secondary outcomes included maximum pain within 24 h, additional analgesia use, and medical abortion effectiveness. 86 women were required in each arm for 90% power to detect a 1.5 point reduction in maximal pain score using an 11-point visual analogue scale (VAS) compared to placebo; the sample size doubled to examine the effect of parity on the primary outcome. Results: 563 women (nulliparous n=275; parous n= 288) were randomized between June 2016 and October 2017. Women in both treatment arms reported lower pain scores compared to placebo (1: 6.43 (95% CI 6.10, 6.75); 2: 6.78 (95% CI 6.10, 6.75); 3: 7.42 (95% CI 7.10, 7.74). Ibuprofen and metoclopramide reduced scores more than tramadol compared to placebo (D mean 1: -0.99 (95% CI -1.45, -0.54); 2: -0.64 (95% CI -1.09, - 0.18); similar results were noted within 24 hours. Nulliparous women reported higher overall pain scores compared to parous women; but, treatment effect was similar. Women receiving prophylactic treatment generally used less additional analgesia. There was no difference in medical abortion effectiveness. Conclusion: Prophylactic ibuprofen and metoclopramide or tramadol reduced pain with medical abortion compared to placebo; ibuprofen and metoclopramide appears to offer better pain control compared to tramadol.