Whether persistent human papillomavirus (HPV) IgG antibodies following natural infection are protective against subsequent infection is unknown. In a cohort of 508 college women followed for 3 y, persistent seropositivity was defined as the presence of type-specific HPV virus-like particle (VLP) antibodies at ≥2 consecutive visits 1 y apart. Protection from incident infection with any HPV was conferred by persistent antibodies to HPV16 (p = 0.02), HPV31 (p < 0.001), HPV33 (p = 0.03), HPV35 (p = 0.002), HPV52 (p = 0.007), HPV45 (p = 0.003), and HPV53 (p = 0.01). The risk of incident infection with species-specific HPV types was also decreased in women with persistent antibodies to any HPV type in that group, suggesting that exposure to HPV with persistent development of antibody response can be protective, and may explain the decreased efficacy of HPV vaccine in women with prior exposure.