OBJECTIVE: The present study systematically reviewed the safety of combined treatment with an alpha blocker and phosphodiesterase-5 inhibitor. MATERIALS AND METHODS: The study was performed according to the PRISMA statement. The included studies were randomized controlled trials that included at least one group on alpha-blocker monotherapy and one group on a combined treatment with an alpha blocker and phosphodiesterase-5 inhibitor. The primary endpoints were the hemodynamic effects of the two groups, specifically the clinically significant changes and a positive orthostatic test. The secondary endpoints were the adverse events of the two treatment modalities. RESULTS: A total of 6687 studies were screened, and 19 randomized controlled trials were eligible for the meta-analysis. The combined treatment more often produced a clinically significant hemodynamic change with an MD of 4.73 (CI 1.25, 17.94; I(2) = 0%; p = 0.02), but the positive orthostatic test was similar between the groups with an MD of 1.64 (CI 0.36, 7.47; I(2) = 50%; p = 0.52). The meta-analysis of adverse events favored alpha-blocker monotherapy with an OD of 0.5 (CI 0.32, 0.78; I(2) = 44%; p = 0.002). However, if we consider only the adverse events due to hypotension, the result was similar between the two groups with an OD of 0.97 (CI 0.58, 1.64; I(2) = 0%; p = 0.92). CONCLUSION: The combined treatment may produce a clinically significant hemodynamic change. The combination of alpha blocker and phosphodiesterase-5 inhibitor was safe because it did not increase the rate of adverse events due to hypotension.