Cost-effectiveness models for infectious diseases like HIV often underestimate the ultimate benefits to society. HIV is a communicable, fatal disease for which there is effective treatment but no cure. Paltiel and colleagues conclude that HIV screening is cost-effective when only the medical benefits to infected patients are considered, which is the usual basis for decisions about practice guidelines. However, they modeled the effects on subsequent transmission primarily on the basis of the potential for antiretroviral therapy to reduce infectiousness. They also restricted their benefit calculations to “first-generation” secondary transmissions—that is, new infections attributable to patients who are already infected, but not subsequent transmissions from the persons they might infect. It is crucial to more accurately quantify the many ramifications of early detection and treatment of HIV on overall transmission dynamics. Most patients, after learning that they are infected, take steps to protect their partners; these steps substantially reduce HIV transmission. The aggregate annual transmission rate for persons unaware of their HIV infection is estimated to be 6.9% compared with 2.0% for persons who are aware (19). This reduction in transmission is similar to that achieved with zidovudine prophylaxis to reduce the risk for perinatal transmission, and could have substantial implications for curbing the HIV epidemic. Many of the essential parameters needed to guide decisions about screening—including the prevalence of undiagnosed HIV infection in specific settings, the optimal frequency for retesting, and the ultimate effects on the course of the epidemic—will be known with certainty only after we implement screening and examine the results.