A case-control study evaluated a possible association between infection with human papillomavirus (HPV) or cytomegalovirus (CMV) and cervical cancer. Seventy-eight patients with cervical cancer (cases) were compared with 55 age-compatible patients with uterine leiomyoma (controls). Genital CMV and HPV infections were diagnosed by polymerase chain reaction amplification of viral DNA in cervical tissues. Smoking, first coitus or pregnancy before age 20, multiple sex partners, history of multiple pregnancies, and frequent sexual intercourse were important factors associated with cervical cancer. Only 9% of the cases versus 29.1% of the controls did not have genital infection with either virus. Concurrent genital CMV and HPV infection was noted in 51.3% of the cases but in none of the controls. HPV infection alone occurred in 15.4% of the cases but in only 5.5% of the controls. CMV infection alone was associated with no increased risk for cervical cancer. These data suggest that a synergistic interaction may occur between these two viral infections in the oncogenesis of cervical cancer.