© 2018 Wolters Kluwer Health, Inc. All rights reserved. Background:Young men who have sex with men (YMSM) experience disparities in HIV acquisition more than any other group. Daily oral pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine has been shown to effectively prevent HIV transmission in YMSM; however, recent studies suggest that young Black men who have sex with men experience subprotective levels of tenofovir diphosphate more frequently than other groups.Setting:Combined data from Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 110/113, 2 open-label PrEP studies that provided PrEP and evidence-based behavioral interventions to YMSM aged 15-22 years.Methods:Bivariate and logistic regression analyses were used to examine sociodemographic and behavioral factors associated with protective tenofovir diphosphate levels (defined as ≥700 fmol/punch) in ATN 110/113 data.Results:In bivariate analysis, self-identified Black participants, residential displacement due to sexual orientation, low perceived risk, and stigma with the medication were associated with subprotective levels. Hispanic ethnicity was associated with protective levels. In the final models, Black males were less likely to have subprotective levels than non-Black males at 4, 8, and 12 weeks. Self-reported displacement due to sexual orientation was associated with subprotective levels, whereas older age was as associated with protective levels.Conclusions:These findings highlight how future behavioral research and biomedical prevention efforts in YMSM will need to address PrEP disparities that may occur in young Black men who have sex with men, perception of risk, and lack of key supportive housing during this period that may be critical factors that contribute to HIV acquisition.