Serology is a useful epidemiological tool to determine past and recent exposure to genital HPV infections and may assist in predicting risk of anogenital HPV-associated cancers and their precursor lesions. We analyzed data from the Ludwig-McGill cohort study to examine the seropositivity for HPV-16 antibodies and its association with different viral and lesion endpoints. The cohort study enrolled 2462 women from Sao Paulo, Brazil, and followed them for more than 10 years to investigate the natural history of cervical HPV infection and precursor cervical lesions. Patients were examined every 4 months during the first year and every 6 months thereafter. Pap cytology and HPV DNA testing were performed in cervical samples and serum specimens collected at most visits. We used an enzyme-linked immunosorbent assay (ELISA) to measure the specific IgG antibody response to HPV-16 virus-like particles (both L1 and L2 capsid proteins). Seropositivity was defined as the upper quintile of average normalized absorbance ratios (NAR) taken at two serum dilutions (1:10 and 1:50) relative to a control serum pool. We used logistic and Cox regressions to assess the associations. HPV-16 seropositivity was strongly associated with HPV-16 DNA in cervical cells. Seroprevalence was higher among HPV-16 DNA-positive (44%) than HPV-16 DNA-negative women (20%). Moderate to strong associations were seen between HPV-16 seropositivity and HPV-16 DNA positivity at baseline [OR = 5.9; 95%CI= 2.2-15.8] and at 1-year period prevalence [OR=3.4; 95%CI=1.9-6.0]. Seropositivity for HPV-16 was consistently predictive of cumulative risk regardless of the timing of outcomes, even after considering different restrictions in the analyses and various positivity cutpoints. Elevated ORs were observed in younger subjects (<33 years), white women, women with multiple sex partners, and those measured with high cervical viral load. A non-statistically significant and weaker serological response was observed for HPV DNA for other HPV types and their associated cervical lesions. In summary, serology is a useful marker of type-specific cumulative HPV exposure and serves as a ancillary tool in epidemiologic studies of the natural history of HPV infection and cervical neoplasia.