The seroepidemiology of genital human papillomavirus (HPV) and incident cervical squamous intraepithelial lesions (SIL) was studied in subjects selected from a large cohort monitored for the development of SIL. Serum IgG and IgA responses to 10 epitopes derived from HPV were measured in 21 incident cases of SIL and 56 matched controls. Cases showed elevated antibody (i.e., IgG and/or IgA) seroprevalence to 245:16, a peptide antigen derived from the E2 open reading frame of HPV 16 (OR = 5.76; 95% CI: 1.24, 26.81). The type of HPV DNA detected in cervical lavage specimens had no effect on this relationship. Multivariate analysis also showed that IgG to 245:6, an analogous peptide derived from HPV 6, was negatively associated with SIL (OR = 0.12; 95% CI: 0.02, 0.77). No other antibody responses tested were associated with SIL. Furthermore, no antibody responses were positively associated with detection of HPV DNA in women without SIL. We conclude that incident SIL is positively associated with antibody to an epitope derived from the E2 region of HPV 16, and negatively associated with antibody to an analogous peptide derived from HPV 6. The seroepidemiology of incident SIL appears different from that of cervical HPV infection in the absence of SIL.