BACKGROUND: A recent randomized, controlled trial showed that daily oral preexposure chemoprophylaxis (PrEP) was effective for HIV prevention in men who have sex with men (MSM). The Centers for Disease Control and Prevention recently provided interim guidance for PrEP in MSM at high risk for HIV. Previous studies did not reach a consistent estimate of its cost-effectiveness. OBJECTIVE: To estimate the effectiveness and cost-effectiveness of PrEP in MSM in the United States. DESIGN: Dynamic model of HIV transmission and progression combined with a detailed economic analysis. DATA SOURCES: Published literature. TARGET POPULATION: MSM aged 13 to 64 years in the United States. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: PrEP was evaluated in both the general MSM population and in high-risk MSM and was assumed to reduce infection risk by 44% on the basis of clinical trial results. OUTCOME MEASURES: New HIV infections, discounted quality-adjusted life-years (QALYs) and costs, and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: Initiating PrEP in 20% of MSM in the United States would reduce new HIV infections by an estimated 13% and result in a gain of 550,166 QALYs over 20 years at a cost of $172,091 per QALY gained. Initiating PrEP in a larger proportion of MSM would prevent more infections but at an increasing cost per QALY gained (up to $216,480 if all MSM receive PrEP). Preexposure chemoprophylaxis in only high-risk MSM can improve cost-effectiveness. For MSM with an average of 5 partners per year, PrEP costs approximately $50,000 per QALY gained. Providing PrEP to all high-risk MSM for 20 years would cost $75 billion more in health care-related costs than the status quo and $600,000 per HIV infection prevented, compared with incremental costs of $95 billion and $2 million per infection prevented for 20% coverage of all MSM. RESULTS OF SENSITIVITY ANALYSIS: PrEP in the general MSM population would cost less than $100,000 per QALY gained if the daily cost of antiretroviral drugs for PrEP was less than $15 or if PrEP efficacy was greater than 75%. LIMITATION: When examining PrEP in high-risk MSM, the investigators did not model a mix of low- and high-risk MSM because of lack of data on mixing patterns. CONCLUSION: PrEP in the general MSM population could prevent a substantial number of HIV infections, but it is expensive. Use in high-risk MSM compares favorably with other interventions that are considered cost-effective but could result in annual PrEP expenditures of more than $4 billion. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse, Department of Veterans Affairs, and National Institute of Allergy and Infectious Diseases.