Background: This retrospective cohort study explores the long-term effects of different endocrine therapy regimens on mortality, local recurrence, and metastasis in breast cancer patients. Methods: Data from the Referral Cancer Research Center of Shahid Beheshti University of Medical Sciences were analyzed. Records of 2,262 histologically confirmed breast cancer patients, with 25 years of follow-up were included. We collected patient data, including treatment modalities, and details of the endocrine therapy, and conducted statistical analysis to assess treatment-outcome associations. Results: Patients had an average age of 49.45 years, and 99.1% were female. The average tumor size was 2.8 cm, with a 12.3% mortality rate. Positive expression of human epidermal growth factor receptor 2, progesterone receptor, and estrogen receptor was found in 17.3%, 71.8%, and 70.6% of patients, respectively. Tamoxifen was administered to 1,700 patients, letrozole to 715, and exemestane to 540, with an average endocrine therapy duration of 5.2 years. Letrozole treatment duration (P = 0.001) and lymph node involvement (P = 0.028) were independent predictive variables for local recurrence, with longer letrozole therapy associated with lower recurrence. Conclusion: Estrogen receptor expression and endocrine therapy duration are independent predictive markers for recurrence and mortality. Longer letrozole therapy predicts lower local recurrence. Endocrine therapy duration inversely relates to mortality, recurrence, and local recurrence.