Background: Cervical human papilloma virus (HPV) detection increases after menopause, but its determinants need clarification.

Methods: In a case–control study nested within a 10,049 women cohort, we evaluated women 45 to 75 years old who acquired HPV infection and were HPV positive 5 to 6 years after enrollment (N = 252), and HPV-negative women as matched controls (N = 265). Detailed sexual behavior and cellular immune response were investigated. Odds ratios (OR) and attributable fractions were estimated.

Results: Women with 2+ lifetime partners had 1.7-fold (95% CI = 1.1–2.7) higher risk than monogamous women, with similar findings if their partners had other partners. Women with 2+ partners after last HPV-negative result had the highest risk (OR = 3.9; 95% CI = 1.2–12.4 compared with 0–1 partners). Weaker immune response to HPV-16 virus-like particles increased risk (OR = 1.7; 95% CI = 1.1–2.7 comparing lowest to highest tertile). Among women with no sexual activity in the period before HPV appearance, reduced immune response to phytohemagglutinin was the only determinant (OR = 2.9; 95% CI = 0.94–8.8). Twenty-one percent of infections were explained by recent sexual behavior, 21% by past sexual behavior, and 12% by reduced immune response.

Conclusions: New infections among older women may result from sexual activity of women and/or their partners or reappearance of past (latent) infections possibly related to weakened immune response.

Impact: HPV infections among older women are associated with current and past sexual exposures and possibly with immune senescence. The risk of cancer from these infections is likely to be low but could not be fully evaluated in the context of this study. Cancer Epidemiol Biomarkers Prev; 19(12); 3044–54. ©2010 AACR.