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This mixed-methods study examined awareness of and willingness to use pre-exposure prophylaxis (PrEP) among sexually active Black and Latinx adolescents (13–17 years) residing in five cities in the United States with some of the highest burden of HIV. Data are from adolescents who participated in a cross-sectional survey (n = 208) and one-on-one interviews and focus groups (n = 26) conducted from September 2017—August 2019. Approximately 50% of the sample were recruited through community efforts, and the other half through a panel. Logistic regression with covariates including sexual orientation, relationship status, socioeconomic status, and race/ethnicity were used to assess factors associated with PrEP awareness and willingness. For the qualitative data, thematic analysis was used to develop a codebook of a-priori and inductive codes while analytic memos were written to identify key themes. PrEP awareness was reported by 38% of the sample and was associated with Black race (AOR = 0.49; 95% CI = 0.27, 0.90) and prior HIV testing (AOR = 3.89, 95% CI = 1.25, 12.08). PrEP willingness (defined as “definitely would use PrEP”) was reported by 22% of the sample and was associated with higher age, more education, having had condomless sex in the past 6 months (AOR = 0.23; 95% CI = 0.10, 0.56), perceived likelihood of acquiring HIV (AOR = 3.59; 95% CI = 1.06, 12.21), and PrEP awareness (AOR = 0.41; 95% CI = 0.19, 0.89). Qualitative data showed that misconceptions about PrEP persist and PrEP stigma, fear of being punished, provider attitudes and recommendations, and empowerment were related to adolescents …