CONTEXT Erectile dysfunction (ED) is a major health care problem worldwide and phosphodiesterase 5 inhibitors (PDE5Is) are the pharmacological treatment of choice. However, the optimal PDE5I for ED treatment is not known. OBJECTIVE To investigate trade-offs between efficacy and adverse events for various PDE5Is in treating ED. EVIDENCE ACQUISITION A review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. Medline, Scopus, reference lists of relevant articles, and systematic reviews were searched. Eligible studies were randomized controlled trials comparing at least one PDE5I for treating ED with placebo or another PDE5I. EVIDENCE SYNTHESIS We included 82 trials (47 626 patients) for efficacy analysis and 72 trials (20 325 patients) for adverse event analysis. In the trade-off analysis of starting dosages, sildenafil 50mg had the greatest efficacy but also had the highest rate of overall adverse events. Tadalafil 10mg had intermediate efficacy but had the lowest overall rate of all adverse events. Vardenafil 10mg and avanafil 100mg had similar overall adverse events than sildenafil 50mg but a markedly lower global efficacy. Udenafil 100mg had similar global efficacy to that of tadalafil 10mg but its overall adverse event rates were higher. CONCLUSIONS This is the first trade-off analysis of the different PDE5Is currently available. For individuals who prioritize high efficacy, sildenafil 50mg appears to be the treatment of choice. Men wishing to optimize tolerability should take tadalafil 10mg or switch to udenafil 100mg in the case of insufficient efficacy. PATIENT SUMMARY For patients with erectile dysfunction who wish to prioritize high efficacy, sildenafil 50mg appears to be the treatment of choice. Men who wish to optimize tolerability should take tadalafil 10mg or switch to udenafil 100mg in the case of insufficient efficacy.