['Human papillomavirus (HPV) infections are suggested to be involved in the development of penile squamous cell carcinoma (SCC), but comprehensive studies to define the association are limited. Therefore, we performed molecular and serologic analyses for a broad spectrum of HPV types on a large series of 83 penile SCCs, and we compared serological findings to those of age-matched male controls (N = 83).', 'Penile SCCs were subjected to detection and typing assays for mucosal and cutaneous HPVs and to subsequent, type-specific viral load and viral gene expression assays. Sera of patients and of controls were analyzed for type-specific mucosal and cutaneous HPV L1, E6, and/or E7 antibodies using bead-based, multiplex serology.', 'HPV DNA of mucosal and/or cutaneous types was found in 46 of 83 (55%) penile SCCs. HPV16 was the predominant type, appearing in 24 (52%) of 46 of penile SCCs. The majority of HPV16 DNA-positive SCCs (18 of 24; 75%) demonstrated E6 transcriptional activity and a high viral load. Additionally, HPV16 molecular findings were strongly associated with HPV16 L1-, E6-, and E7-antibody seropositivity. Furthermore, serologic case-control analyses demonstrated that, in addition to the association of HPV16 with penile SCC, seropositivity against any HPV type was significantly more common in patients compared with in controls. HPV18 and HPV6 seropositivity were associated with HPV16-negative SCCs but were not correlated to molecular findings.'] Is human papillomavirus-16 the predominant type etiologically involved in penile squamous cell carcinoma?