Anal human papillomavirus (HPV) infection is common among women and the cause of most anal malignancies. The incidence of anal cancer has been increasing among U.S. women, yet few cofactors for the natural history of anal HPV infection have been identified. We examined the hypothesis that plasma carotenoid, retinol, and tocopherol concentrations are associated with the acquisition and clearance of anal HPV infection in a cohort of 279 Hawaiian residents followed at 4-month intervals for a mean duration of 16 months. At each visit, interviews were conducted and biological specimens were obtained, including anal cell specimens for HPV DNA detection and genotyping, and a fasting blood sample to measure 27 micronutrients. Cohort participants acquired 189 anal HPV infections, 113 of which cleared during the study period. The most frequently acquired HPV genotypes were HPV-52, -53, -84, and -16. Women in the highest quartile of trans-zeaxanthin, trans -anhydro-lutein, and trans-, cis-, and total β-carotene had significant 43% to 50% reduction in the risk of acquisition of any HPV infection compared with women in the lowest quartile. Few associations were observed between micronutrient levels and clearance of transient (≤ 150 days) anal HPV infections. However, clearance of persistent (> 150 days) infections was associated with higher levels of β-tocopherol + γ-tocopherol and lower levels of carotenoids and retinol. Our findings suggest that several carotenoids can reduce the risk and clearance of anal HPV infections that contribute to anal cancer.