Genital high-risk human papillomaviruses (HPVs) cause cervical cancer and are also found in a small proportion of nonmelanoma skin cancers (NMSCs). We used cancer registry linkages to follow the 856,000 serum donors included in the Southern Sweden Microbiology Biobank or the Janus Biobank in Norway, for incident skin cancers occurring up to 30 years after serum donation. Serum samples taken before diagnosis of squamous cell carcinoma (SCC) (N = 633), basal cell carcinoma (BCC) (N = 1990) or other NMSC (N = 153) and matched samples from control donors were tested for antibodies to the genital HPV types 16 and 18. Both HPV 16 and 18 were associated with increased risk for SCC [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.6 and OR 1.7, 95% CI 1.1-2.5, respectively] and other NMSC (OR 2.3, 95% CI 1.0-5.2 and OR 3.5, 95% CI 1.4-8.7, respectively), but not for BCC. Tumor blocks from HPV16 or 18 seropositive cases were tested with real-time polymerase chain reaction for presence of HPV16 or 18 DNA. No HPV18 DNA was found and only four of 79 SCC cases (two of which were from the perineum/perianal area), one of 221 BCC cases and zero of five cases with other NMSC contained HPV16 DNA. In conclusion, we found prospective evidence that HPV16 and 18 antibodies associate with SCC and other NMSC risk, but not with BCC risk. As only a small proportion of seropositive subjects had evidence of the corresponding HPV DNA in the tumor, most of this excess risk is likely to be due to confounders associated with genital HPV infection.