The etiology of vulvar and vaginal squamous cell carcinoma (VV-SCC) has received little attention. A total of 182 women with invasive VV-SCC (116 with VV-SCCvulva, 66 with VV-SCCvagina), 164 uterine corpus cancer controls and 518 population controls were interviewed in a population-based case–control study in Denmark, and 87 (48%) of the VV-SCC cases had tissue samples examined for human papillomavirus (HPV) DNA using the GP5+/6+ PCR-EIA assay and subsequent reverse line blotting for HPV typing. Logistic regression-derived odds ratios with 95% confidence intervals served as relative risks. Cervical cancer-associated high-risk HPVs (hrHPVs) were detectable in most (89%) examined cases of VV-SCCvagina and in half (50%) of cases of VV-SCCvulva (p < 0.001). In site-specific multivariate logistic regression analyses, statistically significant risk factors for both VV-SCCvulva and VV-SCCvagina included measures of hrHPV exposure (anogenital warts for VV-SCCvulva; cervical neoplasia and poor genital hygiene for VV-SCCvagina), tobacco smoking and alcohol consumption. Furthermore, socioeconomic variables (marital status and years at school) were associated with risk of VV-SCCvulva. Comparing hrHPV-positive and hrHPV-negative VV-SCCs in polytomous logistic regression analysis revealed that tobacco smoking and cervical neoplasia were significant risk factors only for hrHPV-positive VV-SCCs. Our study shows that VV-SCCvulva and VV-SCCvagina share measures of prior hrHPV exposure, tobacco smoking and alcohol consumption as statistically significant risk factors. HPV vaccination programs aimed at reducing the burden of cervical cancers are likely to also provide considerable protection against VV-SCCs. © 2008 Wiley-Liss, Inc.