To evaluate the relationship between use of oral contraceptives and risk of invasive cervical cancer, a case-control study involving 479 patients and 789 population controls was undertaken in 5 geographic regions of the US. Initially, the relationship was obscured by confounding variables, particularly the interval since last Pap smear. Control for this variable as well as for sexual and sociodemographic factors revealed an RR of 1.5 overall, with long-term users (5 or more years) being at a 2-fold higher risk than non-users. Pill associations prevailed for both adenocarcinomas and squamous-cell tumors, and risks were highest for those using pills containing high estrogen potencies. In addition, there was some evidence that pill associations were most pronounced among women who had never used barrier methods of contraception or who had histories of genital infections, suggesting that oral contraceptives may act as co-carcinogens with transmissible agents. Our findings provide further evidence that long-term use of oral contraceptives may have a carcinogenic effect on cervical epithelium, but emphasize the need for careful evaluation of confounding influences.