BACKGROUND: The HIV Prevention Trials Network (HPTN) 067/Alternative Dosing to Augment PrEP Pill Taking (ADAPT) Study evaluated the feasibility of daily and nondaily human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens. METHODS: An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the preexposure prophylaxis initiative (iPrEx) trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use. RESULTS: We estimated that PrEP was highly protective (85%-96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%-88% efficacy) than in Harlem (62%-81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85%, and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8-9 percentage points in Harlem and by 5-9 percentage points in Bangkok across regimens. CONCLUSIONS: Our analysis suggests that PrEP was more effective among MSM in Thailand than in the United States as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, nondaily PrEP was less effective than daily PrEP, especially in the United States where the sex act coverage associated with daily use was substantially higher.