OBJECTIVE To investigate the presence of HPV in VSCC and sentinel nodes (SN) in patients in Sweden and the possible influence of HPV on prognosis. METHODS Primary tumors from 75 VSCC patients undergoing the SN procedure and SNs from 69 patients were tested for HPV DNA. Analyses were performed by PCR using general (GP5+/6+ and CPI/IIG) type-specific primers, and sequencing in paraffin-embedded VSCC and SN. RESULTS HPV was detected in 23/75 (31%) of the tumors and in 10/23 (43%) of the SNs in patients with HPV-positive tumors and in one SN of a patient with an HPV-negative tumor. Patients with HPV-positive VSCC were younger at diagnosis (p<0.001) and had better survival (p=0.030), adjusted for age and lesion size, than those with HPV-negative tumors. In patients with HPV-positive tumors, SNs with metastases were more frequently HPV positive (5/5) than those without metastases (5/18) (p=0.007). CONCLUSIONS The rate of 31% HPV-positive VSCC in Sweden is similar to other reports. As far as we know, HPV in SN in VSCC never been investigated previously. The differences in age, tumor size, prevalence of HPV in SN and survival of patients with HPV-positive and negative VSCC support the assumption that VSCC develops through two different pathways, with better survival for patients with HPV-positive tumors. Presence of HPV DNA in SN was related to metastatic disease but did not affect survival in this study.