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Pre-exposure prophylaxis (PrEP) has the potential to significantly reduce HIV incidence among men who have sex with men (MSM) in the United States. However, the extent to which suboptimal PrEP adherence and retention in care may limit successful implementation is unknown. An agent-based model was used to represent the entire population of MSM in Rhode Island from 2013 to 2017. The impact of potential interventions to improve PrEP adherence and retention in care on HIV transmission was evaluated. Demographics, behaviors, and PrEP adherence and retention in care rates were based on local clinical data. We assumed that 20% of HIV-negative MSM had ever taken PrEP. The primary outcome was HIV incidence over the 5-year period. The model included 23,815 MSM with an estimated 4.1% HIV prevalence based on local surveillance data. An estimated 173.1 new infections occurred over 5 years [95% simulation interval (SI): 171.5–174.7], including 29.1 new infections among individuals who had ever initiated PrEP (95% SI: 28.6–29.7). Interventions that improved retention in PrEP care by an odds of 5.0 compared with the base case maximized reductions in HIV incidence among MSM who had ever initiated PrEP by 37.5%. Interventions focusing on improving PrEP adherence had little to no effect on HIV incidence, regardless of intervention efficacy. Retention in care is a critical component of the PrEP care continuum. Interventions that improve retention in PrEP care may lead to greater reductions in population-level HIV incidence compared with interventions focused exclusively on adherence. [ABSTRACT FROM AUTHOR]