Infection with high-risk human papillomavirus (HPV) is considered a “necessary cause” for cervical cancer (CC); however, only some HPV-infected women develop CC. We report on the differential risk contribution of sexual behavior and cigarette smoking to cervical neoplasia in the US and Venezuela. A total of 142 patients and 158 matched-controls were recruited from both countries using the same recruitment protocol, the same pathologists for case verification, and the same experimental procedures for analysis. HPV infection was significantly associated with CC for both populations as expected, but the Venezuelan controls were twice as likely to be infected with HPV as the US controls. Having >2 lifetime sexual partners (OR = 4.7, 95% CI = 1.7-13.1) and initiation of sexual activities before the age of 18 (OR = 4.7, 95% CI = 1.6-13.7) were significant risk factors in a multivariate model for CC in Venezuela. In contrast, current cigarette smoking was a significant risk factor only in the US (OR = 3.6, 95% CI = 1.7-7.7). The observed differences in risk factors support the need for additional studies in different geographic regions and the information can be used to develop country-specific CC prevention programs.