Objective To compare 400 and 800 g sublingual or vaginal misoprostol 24 hours after 200 mg mifepristone for noninferiority regarding efficacy in achieving complete abortion for pregnancy termination up to 63 days of gestation. Design Placebo-controlled, randomised, noninferiority factorial trial, stratified by centre and length of gestation. Misoprostol 400 or 800 g, administered either sublingually or vaginally, with follow up after 2 and 6 weeks. Setting Fifteen obstetricsgynaecology departments in ten countries. Population Pregnant women (n = 3005) up to 63 days of gestation requesting medical abortion. Methods Two-sided 95% CI for differences in failure of complete abortion and continuing pregnancy, with a 3% noninferiority margin, were calculated. Proportions of women with adverse effects were recorded. Outcome measures Complete abortion without surgical intervention (main); continuing live pregnancies, induction-to-abortion interval, adverse effects, women's perceptions (secondary). Results Efficacy outcomes analysed for 2962 women (98.6%): 90.5% had complete abortion after 400 g misoprostol, 94.2% after 800 g. Noninferiority of 400 g misoprostol was not demonstrated for failure of complete abortion (difference: 3.7%; 95% CI 1.8-5.6%). The 400-g dose showed higher risk of incomplete abortion (P < 0.01) and continuing pregnancy (P < 0.01) than 800 g. Vaginal and sublingual routes had similar risks of failure to achieve complete abortion (P = 0.47, difference in sublingual minus vaginal -0.7%, 95% CI -2.6-1.2%). A similar pattern was observed for continuing pregnancies (P = 0.21). Fewer women reported adverse effects with vaginal than sublingual administration and with the 400-g dose than the 800-g dose. Of the women, 94% were satisfied or highly satisfied with the regimens, 53% preferred the sublingual route and 47% preferred the vaginal route. Conclusions A 400-g dose of misoprostol should not replace the 800-g dose when administered 24 hours after 200 mg mifepristone for inducing abortion in pregnancies up to 63 days. Sublingual and vaginal misoprostol have similar efficacy, but vaginal administration is associated with a lower frequency of adverse effects. © RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology.