BACKGROUND: Aromatase inhibitors have demonstrated superior outcomes compared to tamoxifen in various studies. However, research in Africa, including Kenya, where breast cancer mortality rates are disproportionately high, is lacking. OBJECTIVES: The study aimed to assess the comparative efficacy of tamoxifen and aromatase inhibitors among hormone receptor-positive breast cancer patients at Kenyatta National Hospital. METHODS: A retrospective cohort study was conducted at the Oncology Department of Kenyatta National Hospital, involving all eligible hormone receptor-positive breast cancer patients treated in the facility between 1st January 2019 to 31st December 2022. The study was hospital-based and used a data abstraction tool to collect data from the patients' medical records. The data obtained was then analyzed using SPSS version 25 and Kaplan-Meier analysis was used to estimate the median survival time. Cox regression analysis was employed to determine whether there was a significant association between the variables. The collected data was presented in the form of frequency tables and graphs. RESULTS: In our study, aromatase inhibitors consistently demonstrated superior outcomes compared to tamoxifen across various parameters. Specifically, aromatase inhibitors showed a lower incidence of disease progression (24% vs. 29.7%), a higher rate of complete radiological response (24% vs. 13.5%), and a reduced likelihood of developing distant metastasis while on treatment, coupled with a lower mortality rate (40% vs. 48.0%). Additionally, the median survival time for patients receiving aromatase inhibitors was notably longer at 49.0 months compared to 42.0 ± 3.6 months for those on tamoxifen (P = 0.410). Similarly, the aromatase inhibitor group exhibited a more extended median metastasis-free survival time (42.0 months vs. 30.0 ± 1.4 months, P = 0.056) and a more favorable survival time from metastasis to death (8 ± 0.6 months vs. 6 ± 0.8 months in the tamoxifen group, P = 0.142). CONCLUSION: These findings collectively suggest a consistent trend towards improved treatment outcomes with aromatase inhibitors compared to tamoxifen. The observed reduction in mortality rates among aromatase inhibitor-treated patients highlights their potential clinical benefit, with superior overall survival and disease progression.