We used a dynamic, compartmental model of the sexually active U.S population to estimate the impact of delivering pre-exposure prophylaxis (PrEP) to persons at high risk of acquiring HIV in individual transmission groups (men who have sex with men, persons who inject drugs, heterosexual males, and heterosexual females). In alternative scenarios, we modeled the application of PrEP to high-risk persons in each transmission group, and we assessed the number of infections averted across all transmission groups, the number of people on PrEP per infection averted, and the total cost incurred from 2020 through 2024.