Background For the target of oral erectile dysfunction drugs, phosphodiesterase type 5 (PDE5) inhibitors (Viagra), are part of a pathway closely associated with the development of malignant melanoma. An increased risk of malignant melanoma in sildenafil users has been recently reported. Significance To examine the association between the use of PDE5 inhibitors and melanoma risk, including data on specific PDE5 inhibitors, prescription numbers, and stage of melanoma. Methods A nationwide, population-based, nested case-control study was conducted in the Swedish Prescription Drug Register, the Swedish Melanoma Register, and other health care registries, and in the Swedish population database, including 4065 melanoma cases diagnosed from 2006 to 2012, and 5 randomly selected control cases matched for their year of birth. Exposure points were the number of prescriptions filled for the PDE5 inhibitors sildenafil and vardenafil or tadalafil. The primary outcome was the risk of melanoma and the stage and risk of basal cell carcinoma in multivariate logistic regression analysis. Results Of the 4065 melanoma cases, 435 (11%) of the male prescriptions were filled with PDE5 inhibitors, as were 1713 patients (8%) of the 20325 controls. In multivariate analysis, men taking PDE5 inhibitors had an increased risk of melanoma (OR, 1.21 [95% Cl, 1.08-1.36]). The most significant increased risk was observed in men with a single prescription (OR, 1.32 [95% Cl, 1.10-1.59]; exposure, 4% in cases vs. 3% in controls), whereas it was not significant in men with multiple filled prescriptions (2-5 prescriptions: OR, 1.14 [95% CIl, 0.95-1.37], 4% in cases vs. 3% in controls; For ≥6 prescriptions: OR, 1.17 [95% Cl, 0.95-1.44], 3% of cases vs. 2% of controls). PDE5 inhibitors were associated with melanoma stage 0 (OR, 1.49 [95% Cl, 1.22-1.83], 13% of cases vs. 8% of controls) and stage I (OR, 1.21 [95% Cl, 1.02- 1.43] 12% in cases vs. 10% in controls) but not with Stage II to IV courses (OR 0.83 [95% Cl, 0.63-1.09], 6% in cases vs. 7% in controls). Risk estimates were similar for sildenafil and vardenafil or tadalafil. the use of PDE5 inhibitors was also associated with an increased risk of basal cell carcinoma (OR, 1.19 [95% Cl, 1.14-1.25], 9% of cases vs 8% of controls). Men taking PDE5 inhibitors had higher educational attainment and annual income, factors that were also significantly associated with melanoma risk.