PROJECT SUMMARY/ABSTRACT Emerging data indicates that doxycycline prophylaxis (doxyPEP) may be a promising strategy to prevent bacterial STIs. Open-label studies among SMM found that doxycycline 200mg within 72 hours of STI exposure reduced gonorrhea, chlamydia, and syphilis infection by 47-66% among SMM in the United States and France. However, the only data surrounding doxyPEP in cisgender women did not show an impact on STI incidence rates, due to low adherence. While local and state-level public health agencies have advocated for the use of doxyPEP among SMM and trans women with increased likelihood for STIs, these recommendations have not yet been uniformly extended to people AFAB due to lack of data. This study seeks to address this gap by evaluating the acceptability, efficacy, tolerability, and adherence of doxyPEP among young and adolescent people AFAB at increased likelihood of STI exposure through the following aims: Aim 1: Evaluate the efficacy of doxyPEP (both on-demand and weekly dosing) in reducing incident bacterial STIs, compared to standard of care (quarterly STI testing and treatment) among adolescent and young people AFAB; Aim 2: Assess the acceptability and tolerability of doxyPEP among adolescent and young AFAB; Aim 3: Evaluate self-reported adherence and objective use of doxyPEP; Aim 4: Determine the impact of doxyPEP on prevalence of tetracycline resistance in Staphylococcus aureus and Neisseria gonorrhoeae. To achieve these aims, participants will be randomized 1:1:1 to 1) on-demand doxyPEP (doxycycline 200mg within 72 hours of condomless sex), 2) weekly doxyPEP (doxycycline 200mg weekly regardless of sexual exposure), or 3) standard of care (quarterly STI testing and treatment). Participants will participate in quarterly study visits that will consist of sexual behavior surveys, STI testing, and specimen collection, including plasma and hair samples to measure systemic doxycycline levels to assess for objective markers of adherence. Participants will additionally utilize the HealthMPowerment mobile app to promote engagement and adherence as well as to complete weekly surveys evaluating sexual behavior and doxycycline use.