BackgroundSubstance use among adolescent girls is associated with numerous risk characteristics, including engaging in sexual risk behaviors, which can lead to HIV and sexually transmitted infection (STI) diagnoses. This is an important phenomenon to target as there is a significant race-gendered paradox that occurs when Black girls use and misuse drugs. When misuse occurs among this group, they are more likely to face harsher consequences and worse health outcomes than boys and other ethnic-minority girls. Therefore, there is a need to understand the risk and protective factors of drug use and sexual risk behaviors among Black girls and develop a robust intervention that can cater for this group. ObjectiveWe propose the development of a strengths-based prevention education intervention for Black girls between the ages of 13 and 18 years to promote protective factors. MethodsA sequential, mixed methods study will be conducted, and we will use the first 3 steps of the ADAPT-ITT (assessment, decision, adaptation, production, topical experts, integration, training, testing) framework to begin the development of the intervention. Three aims will be described in this protocol. First, aim 1 is to explore sociocultural risk and protective factors among Black girls between the ages 13 and 18 years in drug use and HIV/STI prevention using focus group methodology and surveys. We will conduct at least 10 focus groups to include up to 75 Black girls or until we reach saturation. Our target sample size for the quantitative portion of the study will be 200 participants. Aim 2 will focus on deciding upon an intervention based on findings from aim 1 and forming a youth advisory board to guide intervention development. Aim 3 will be to conduct a pretest of the intervention with the youth advisory board to determine if the intervention is feasible and will be accepted by Black girls. ResultsThe study is part of a 2-year research pilot study award from the National Institutes of Mental Health. Data collection for this study began in October 2021. For aim 1, data collection is 95% complete. We expect to complete all data collection for aim 1 on or before May 30, 2023. Study activities for aim 2 are occurring simultaneously as data are being collected and analyzed and will be completed in the summer of 2023. Study activities for aim 3 will begin in the fall of 2023. ConclusionsThis study will be one of the few interventions that address both sexual health and drug use together and cater to Black girls. We anticipate that the intervention will be beneficial for Black girls across the nation to work on building culturally appropriate prevention education and building peer social supports, resulting in reduction or delayed substance use and improved sexual health. Trial RegistrationClinicalTrials.gov NCT05014074; https://clinicaltrials.gov/ct2/show/NCT05014074 International Registered Report Identifier (IRRID)DERR1-10.2196/45007