Little is known about penile carcinogenesis. The aim of this study was to evaluate the prevalence of HPV and EBV, and the methylation status of p16^ink4a in penile cancer samples, and to contribute to the understanding of the mechanisms responsible for penile cancer development. HPV DNA was detected in 63.6% of 122 cases, with HPV16 being the most prevalent type. EBV DNA was detected in 47.7%, with EBV‐1 being the most prevalent type. HPV/EBV co‐infections were found in 27.3% of the cases. Hypermethylation in p16^ink4a was detected in 64.5% of 110 tested cases. An association between the absence of HPV absence and p16^ink4a hypermethylation was also found. Death and/or progressive disease was associated with grade (P = 0.001), T stage (P < 0.0001), and N stage (P < 0.0001). In the multivariable model, grade and N stage were independent risk factors for disease‐free survival (P = 0.008 and P < 0.001, respectively). Patients without viral infection had a median age significantly lower than that of the HPV‐infected patients. We suggest at least two pathways for penile carcinogenesis, one HPV‐independent linked to epigenetic events, probably via p16^ink4a inactivation; and another, dependent on HPV infection.