About 50,000 people are infected with HIV in the US each year and this number has remained virtually the same for the past decade. Yet, in the last few years, evidence from several multinational randomized clinical trials has shown that the provision of antiretroviral drug to uninfected persons (i.e. pre-exposure prophylaxis) reduces the incidence of HIV by about 50 %. However, evidence from cost-effectiveness studies conducted in the US yield widely varying estimates of the cost per quality-adjusted life-year (QALY) gained, and this variation reflects the substantial uncertainty surrounding the determinants of HIV transmission (e.g. adherence rates to prophylactic medications, the average number of sexual partners, the number and types of sexual acts, the viral load of infected partners, and the proportion of contacts where condoms are used), as well as different approaches to translating a reduction in HIV cases into an estimate of the increase in the number of QALYs.