BACKGROUND: Most cancers of the uterine cervix are squamous cell carcinomas. Although the incidence of such carcinomas of the uterine cervix has declined over time, that of cervical adenocarcinoma has risen in recent years. The extent to which human papillomavirus (HPV) infection and cofactors may explain this differential trend is unclear. METHODS: We pooled data from eight case-control studies of cervical cancer that were conducted on three continents. A total of 167 case patients with invasive cervical adenocarcinoma (112 with adenocarcinoma and 55 with adenosquamous carcinoma) and 1881 hospital-based control subjects were included. HPV DNA was analyzed in cervical specimens with the GP5+/6+ general primer system followed by type-specific hybridization for 33 HPV genotypes. Blood samples were analyzed for chlamydial and herpes simplex virus 2 (HSV-2) serology. Multivariable unconditional logistic regression modeling was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). All tests of statistical significance were two-sided. RESULTS: The adjusted overall odds ratio for cervical adenocarcinoma in HPV-positive women compared with HPV-negative women was 81.3 (95% CI = 42.0 to 157.1). HPV 16 and HPV 18 were the two most commonly detected HPV types in case patients and control subjects. These two types were present in 82% of the patients. Cofactors that showed clear statistically significant positive associations with cervical adenocarcinoma overall and among HPV-positive women included never schooling, poor hygiene, sexual behavior-related variables, long-term use of hormonal contraception, high parity, and HSV-2 seropositivity. Parity had a weaker association with adenocarcinoma and only among HPV-positive women. Use of an intrauterine device (IUD) had a statistically significant inverse association with risk of adenocarcinoma (for ever use of an IUD compared with never use, OR = .41 [95% CI = 0.18 to 0.93]). Smoking and chlamydial seropositivity were not associated with disease. CONCLUSIONS: HPV appears to be the key risk factor for cervical adenocarcinoma. HPV testing in primary screening using current mixtures of HPV types and HPV vaccination against main HPV types should reduce the incidence of this cancer worldwide.