It is well established that infection with high-risk types of human papillomavirus (HPV) is central to the pathogenesis of invasive cervical cancer. However, many women are infected with high-risk types of HPV, but only a subset of infected women will ever develop cervical cancer, suggesting that other cofactors must be present for the development of malignancy. Prior to the discovery of HPV, both Chlamydia and herpes simplex virus-2 (HSV-2) were postulated to be the sexuallytransmitted infections that are important for the development of invasive cervical cancer; however, it is now thought that these associations were likely confounded by the inability to account for the contribution of HPV infection to the risk of invasive cervical cancer. In this issue of the Journal, Smith and colleagues (1) present a well-designed case–control study demonstrating that, among women infected with high-risk types of HPV, serologic evidence of past HSV-2 infection is associated with an approximately twofold increased risk of invasive cervical cancer. This study is the latest of a series of studies that have used sensitive and specific polymerase chain reaction-based methods to detect HPV and other agents that cause genital infections and that, after appropriate adjustment for detection, type, persistence, and level of HPV, have found an association between the risk of cervical cancer and sexually transmitted infections