Sexually transmitted genital human papillomavirus (HPV) infection, most often HPV 16, is considered the major etiologic determinant of cervical cancer. However, some studies have found relatively low prevalences of genital tract HPV DNA in some geographical areas, such as Greenland, that have high rates of cervical cancer. We sought to evaluate HPV 16 infection in high-risk cohorts using a serologic assay that assesses prior exposure as well as current infection and to compare the results with those obtained using a sensitive PCR-based HPV DNA assay. An ELISA based on HPV 16 virus-like particles was used to detect IgG serum antibodies in women attending sexually transmitted disease (STD) clinics in Nuuk, Greenland and Copenhagen, Denmark. Using a preassigned cut-off, 56% of Greenlandic and 41% of Danish women were seropositive (p = 0.02). In Greenlandic women, there was a non-significant increase in seropositivity with age, and odds ratios for seropositivity were similar for women with more than 5 lifetime sex partners. Seropositivity in the Danish women, however, increased linearly with increases in these 2 factors, which are likely correlates of lifetime exposure to genital HPVs. In contrast, any genital HPV DNA (HPV16 specifically) was detected in 24% and 36% of Greenlandic and Danish women, respectively and was most frequently detected in women below 20. The finding that HPV DNA prevalences, unlike seroprevalences, tended to decrease with increased lifetime risk of infection, provides an explanation for the lack of correlation between HPV DNA prevalences and cervical cancer risk in previous studies of high-risk populations.