BACKGROUND: Various medical methods for second-trimester medical termination of pregnancy (MTP) exist. Misoprostol alone has been used with myriad variations in route and dosage. Comparison between oral and vaginal routes of misoprostol forms the basis of this study. METHODS: This was a prospective comparative study of misoprostol for second-trimester (14-20 weeks) MTP, comparing oral versus vaginal routes. Sixty patients were randomly allotted to two groups; 30 received oral misoprostol 400 µg 4 h up to a maximum of five doses (2000 µg), and 30 received vaginal misoprostol in the same dose and duration. In both groups, oxytocin infusion was started if abortion did not occur. Efficacy of oral versus vaginal misoprostol, induction-abortion interval (AI) and need for surgical intervention were analyzed. RESULTS: Both groups were well matched in terms of age, parity, previous LSCS, mean gestational age and indication for MTP. Overall mean induction-abortion interval was 19.59 h (21.66 vs. 18.57 h, oral vs. vaginal, respectively), with vaginal group taking lesser time (p 0.09). Sixty percentage in oral group required five doses, while 70% in vaginal group required 3-4 doses of misoprostol (p 0.010). 23.7 versus 6.7% in oral versus vaginal group required check curettage (p 0.038). There were no major complications, and there was only one failure in oral group. CONCLUSIONS: Though both oral and vaginal misoprostol are safe, vaginal route appears to be more efficacious for second-trimester MTP.