© 2021 Japan Society of Obstetrics and Gynecology.Purpose: We sought to compare the efficacy of the letrozole (LTZ) stair-step protocol with clomiphene citrate (CC) stair-step protocol in the management of 150 mg dose of CC-resistant polycystic ovary syndrome (PCOS) patients. Methods: We retrospectively compared a total of 61 patients diagnosed as being resistant to the traditional CC protocol who were subsequently managed using the LTZ stair-step protocol with CC-resistant 56 patients who were treated with CC stair-step protocol. The number of follicles ≥18 mm, endometrial thickness, time to ovulation, clinical pregnancy rates, multiple pregnancy rates, spontaneous abortion rates, live birth rates, and systemic side effects in patients were evaluated. Results: The mean time to ovulation was significantly shorter in the LTZ stair-step group than the CC stair-step group (17.3 ± 7.7 and 22.4 ± 8.1 days, respectively, p < 0.001). The ovulation rate was significantly higher in patients treated with LTZ stair-step protocol than those treated with the CC stair-step protocol (83.6% and 64.2%, respectively, p = 0.007). The clinical pregnancy rate was higher in the LTZ stair-step than the CC stair-step group (32.7% and 17.8%, respectively, p = 0.015). LTZ stair-step group had a significantly higher live birth rate than that of the CC stair-step group (27.8% and 14.2%, respectively, p = 0.012). Conclusion: The LTZ stair-step protocol revealed higher ovulation, clinical pregnancy, and live birth rates with a shorter time to achieve ovulation than the CC stair-step protocol. Increment of the dose in the same cycle in both protocols did not cause any additional severe side effects.