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Background: Uptake of pre-exposure prophylaxis (PrEP) in the United States (US) remains below target, despite reported high efficacy in prevention of HIV infection and being considered as a strategy for ending new HIV transmissions. Here, we sought to investigate drivers for PrEP use and barriers to increased uptake using real-world data. Methods: Data were drawn from the Adelphi PrEP Disease Specific Programme™, a cross-sectional survey of PrEP users and PrEP non-users at risk for HIV and their physicians in the US between August 2021 and March 2022. Physicians reported demographic data, clinical characteristics, and motivations for prescribing PrEP. PrEP users and non-users reported reasons for or against PrEP use, respectively. Bivariate analyses were performed to compare characteris tics of users and non-users. Results: In total, 61 physicians reported data on 480 PrEP users and 121 non-users. Mean ± standard deviation of age of users and non-users was 35.3 ± 10.8 and 32.5 ± 10.8 years, respectively. Majority were male and men who have sex with men. Overall, 90.0% of users were taking PrEP daily and reported fear of contracting HIV (79.0%) and having at-risk behaviors as the main drivers of PrEP usage. About half of non-users (49.0%) were reported by physicians as choosing not to start PrEP due to not wanting long-term medication. PrEP stigma was a concern for both users (50.0%) and non-users (65.0%). More than half felt that remembering to take PrEP (57.0%) and the required level of monitoring (63.0%) were burdensome. Conclusions: Almost half of people at risk for HIV were not taking PrEP due to not wanting long-term daily medication and about half of current PrEP users were not completely adherent. The most common reason for suboptimal adherence was forgetting to take medication. This study highlighted drivers for PrEP uptake from physician, PrEP user, and non-user perspectives as well as the attributes needed in PrEP products to aid increased PrEP uptake.