OBJECTIVE:: To compare the efficacy of the vaginal and sublingual administration of the synthetic prostaglandin misoprostol with the currently used oral administration route in second-trimester medical abortion. METHODS:: This was a prospective randomized trial of medical abortion with misoprostol after mifepristone priming at 14-24 weeks of gestation. From 2009 to 2013, recruited women received 200 mg mifepristone orally followed 24-48 hours later by an 800-microgram vaginal loading dose of misoprostol. Women were then randomized to receive additional 400-microgram misoprostol doses orally every 3 hours, vaginally every 4 hours, or sublingually every 3 hours. The main outcome was the duration of abortion with emphasis on the proportion of women undelivered 12 hours after the misoprostol loading dose in the three groups. RESULTS:: A total of 302 women were randomized: 100 to oral, 100 to vaginal, and 102 to sublingual misoprostol. The median gestation at recruitment was oral 19.1 weeks (interquartile range 17.2-20.8), vaginal 19.4 weeks (interquartile range 17.3-20.4), and sublingual 19.7 weeks (interquartile range 17.6-21.0). The overall abortion duration was longer in women receiving oral misoprostol: oral 9.5 hours (95% confidence interval [CI] 8.5-11.4), vaginal 7.4 hours (95% CI 6.5-8.2), and sublingual 7.8 hours (95% CI 7.0-9.2). Overall, 84 of 302 (27.8%) women were undelivered at 12 hours, comprising 37.0% (95% CI 28.7-47.8) oral, 20.5% (95% CI 14.0-30.1) vaginal, and 21.0% (95% CI 14.3-30.7) sublingual groups. CONCLUSION:: Vaginal or sublingual misoprostol administered after a vaginal loading dose in second-trimester medical abortion with mifepristone priming is associated with a shorter time to pregnancy termination compared with an oral regimen. © 2014 by The American College of Obstetricians and Gynecologists.