The association between seropositivity to virus-like particles (VLP) of human papillomavirus (HPV) types 16, 18, 31, 35, or 45 and subsequent cervical HPV infection was examined in 829 women with HIV and 413 risk-matched HIV-negative women. We found no statistically significant differences between HPV-seropositive and HPV-seronegative women in the risk of a new infection with the homologous HPV type, with the exception of a reduced risk of HPV 45 infections 4.5 years beyond the baseline serology measurement in HIV-positive women [hazard ratio, 0.21; 95% confidence interval (CI), 0.05-0.89]. Among HIV-negative women, HPV seropositivity was not associated with a statistically significant reduced risk of infections with related viruses in the HPV 16, HPV 18, or "other" HPV groups. Among HIV-positive women, HPV seropositivity was associated with a slightly increased risk of infection with group-related viruses, but the differences were only statistically significant for infection with HPV 16 group viruses (hazard ratio, 1.6; 95% CI, 1.1-2.3) in HPV 18-seropositive women and for infections with "other" HPV group viruses in HPV 31-seropositive women (hazard ratio, 1.45; 95% CI, 1.0-2.0). The lack of a protective immune effect from natural infection is most likely due to the low level of antibody elicited by natural HPV infection and/or the potential for reactivation of HPV, especially in HIV-positive women.