304 Background: Androgen-deprivation therapy (ADT) through surgical castration is equally effective as medical castration in controlling prostate cancer (PCa). However, the adverse effect profiles of both ADT groups have never been compared. Our objective was to provide a comparative effectiveness analysis of the adverse effects of gonadotropin-releasing hormone agonists (GnRHa) vs. bilateral orchiectomy in a homogeneous population. Methods: A total of 3295 men with metastatic PCa aged ≥ 66 years old, treated with GnRHa or bilateral orchiectomy between 1995 and 2009 were identified. Multivariable competing-risks regression models were performed, with the adjustment of all-cause mortality and treatment propensity score. Secondary analyses examined the effect of increasing duration of GnRHa treatment, and expenditures. Our main examined measures were: [1] any fractures, [2] peripheral arterial disease, [3] venous thromboembolism, [4] cardiac-related complications, [5] diabetes mellitus, [6] cognitive disorders, and [7] total expenditures. Results: In adjusted analyses, orchiectomy was associated with significantly lower risks of any fracture (HR: 0.80, 95% CI: 0.65–0.97), peripheral arterial disease (HR: 0.70, 95% CI: 0.53–0.92), and cardiac-related complications (HR: 0.82, 95% CI: 0.69–0.97) compared to those treated with GnRHa. No statistically significant difference was noted between orchiectomy and GnRHa for diabetes and cognitive disorders. When compared to individuals treated for ≥ 35 months with GnRHa, the increased risk for GnRHa compared to orchiectomy was noted for fractures, peripheral arterial disease, venous thromboembolism, cardiac-related complications, and diabetes mellitus (HR: 1.69, 2.19, 1.60, 1.62, and 1.36, respectively, all P≤ 0.04). No difference with respect to total expenditures was observed between GnRHa and orchiectomy (odds ratio [OR]: 1.21, 95% CI: 0.92–1.58). Conclusions: GnRHa was associated with higher risks in 3/7 examined adverse effects: any fractures, peripheral arterial disease rates, and cardiac-related complications.