High serum levels of insulin-like growth factor-I (IGF-I) are reported to be a risk factor for several common cancers, and recent cross-sectional data suggest a possible additional association of IGF-I with cervical neoplasia. To prospectively assess whether circulating IGF-I levels influence the natural history of oncogenic human papillomavirus (HPV), the viral cause of cervical cancer, we conducted a pilot investigation of 137 women who underwent semiannual type specific HPV DNA PCR testing and cervical cytology. Total IGF-I and IGF binding protein-3 (IGFBP-3), the most abundant IGFBP in circulation, were measured using baseline serum specimens. Having a high IGF-I/ IGFBP-3 ratio was associated with increased persistence of oncogenic HPV infection [that is, a lower rate of clearance; adjusted hazard ratio (AHR), 0.14; 95% confidence interval (95% CI), 0.04-0.57], whereas IGFBP-3 was inversely associated with both the incident detection of oncogenic HPV (AHR, 0.35; 95% CI, 0.13-0.93) and the incidence of oncogenic HPV-positive cervical neoplasia (that is, squamous intraepithelial lesions at risk of progression; AHR, 0.07; 95% CI, 0.01-0.66). These prospective data provide initial evidence that the IGF axis may influence the natural history of oncogenic HPV.