OBJECTIVE: The aim of the study was to compare the efficacy and safety of two combined misoprostol regimens for second trimester medical abortion.METHODS: This was a retrospective cohort study examining data on singleton pregnancies that underwent second trimester medical abortion between November 2011 and November 2019 in a tertiary care centre in northern Greece. In the first study period (November 2011 to August 2015), the management protocol (protocol 1) consisted of 800 μg vaginal misoprostol followed by 400 μg oral misoprostol, every 3 h, for up to five doses. In the second study period (September 2015 to November 2019), a new protocol (protocol 2) was introduced, where the oral route was changed to sublingual, using the same dosage. The two routes were compared in terms of efficacy and safety.RESULTS: The study comprised 85 women: 43 (50.6%) received the protocol 1 regimen (vaginal-oral), while 42 (49.4%) received the protocol 2 regimen (vaginal-sublingual). The groups did not differ in terms of maternal age, gestational age and parity. Sublingual misoprostol was more effective than oral misoprostol, both in terms of dose needed (median 1600 μg vs 2000 μg;  = 0.031) and induction-to-abortion interval (8 h vs 11 h;  = 0.001). Surgical evacuation due to incomplete abortion was necessary in 11.9% of women in the sublingual group vs 18.6% in the oral group ( = 0.394). Women in the sublingual group reported a higher rate of severe pain (odds ratio [OR] 6.061; 95% confidence interval [95% CI] 1.240, 29.619) and shivering (OR 4.632; 95% CI 1.788, 11.995).CONCLUSION: The administration of vaginal-sublingual misoprostol, when compared with the vaginal-oral regimen, was associated with a shorter induction-to-abortion interval but a higher incidence of severe pain and shivering.