Second-trimester medical abortion is a crucial healthcare service, but the standard treatment, misoprostol, has limitations in terms of efficacy and safety. Objective: The aim of this study was to compare the efficacy and safety of using letrozole as a pretreatment for second-trimester medical complete abortion with misoprostol alone. Method: A prospective cohort study was conducted from February 2022 to October 2023. Eligible participants were women aged 18 years or older with gestational ages between 16 and 20 weeks. The patients were divided into two groups: 35 patients in the misoprostol-only group and 35 patients in the letrozole/misoprostol group. The primary outcome was the expulsion of the fetus in the first 72 hours, and secondary outcomes included time to complete and incomplete expulsions, the need for interference after 72 hours, the severity of bleeding, and the severity of pain. Results: The letrozole/misoprostol group had a significantly higher rate of complete expulsion within 72 hours compared to the misoprostol-only group (74.29% vs. 40.00%). The mean time to complete expulsion was significantly shorter in the letrozole/misoprostol group than in the misoprostol-only group (23.61 hours vs. 47.28 hours). The need for interference after 72 hours was significantly lower in the letrozole/misoprostol group than in the misoprostol-only group (5.71% vs. 22.86%). The study found no significant difference between the two groups in terms of the severity of bleeding or pain. The adjusted odds ratio for spontaneous complete expulsion in association with the use of letrozole was 4.16 (95% CI, 1.43 - 12.08; P=0.009), and the adjusted odds ratio for the need for interference after 72 hours in association with the use of letrozole was 0.16 (95% CI, 0.03 - 0.99; P=0.049). Conclusion: The study findings suggest that the use of letrozole as a pretreatment for second-trimester medical abortion is safe and effective.