Background: Phosphodiesterase type 5 inhibitor (PE5i) administration may stimulate the proliferation and survival of melanocytes. However, discrepancies remain regarding the association between PDE5i use and melanoma risk in observational studies in humans. Aim: To evaluate the association between PDE5i use and melanoma in a meta-analysis. Materials and methods: Studies were identified by searching the PubMed and Embase databases. A random-effects model was applied to synthesize the data. A stratified study was performed to evaluate the influence of study characteristics on outcomes. Results: Four prospective cohort studies and three case-control studies with 1,534,615 male participants and 16,053 melanoma cases were incorporated. Patients who received a PDE5i had a significantly increased risk for melanoma (adjusted risk ratio [RR] = 1.12, 95% CI = 1.03-1.33, P=0.008) with moderate heterogeneity (I-2=54%). Cohort studies (adjusted RR = 1.22, 95% CI = 1.02-1.46, P=0.03) largely contributed to this result rather than case-control studies. Subsequent stratified analyses revealed that sildenafil was associated with an increased risk of melanoma (adjusted RR = 1.26, 95% CI = 1.07-1.50, P=0.007), but tadalafil and vardenafil were not. Also, PDE5i use was associated with a significantly increased risk of in situ melanoma (adjusted RR = 1.31, 95% CI = 1.01-1.69, P=0.04), but not of localized or nonlocalized melanoma. Conclusion: PDE5i use may be associated with a significantly increased risk for melanoma in men. However, further research is needed to determine whether the association is causative.