ABSTRACT Reducing new HIV and STI infections among South African (SA) adolescent girls and young women (AGYW) is global public health priority.1 SA has world's largest HIV epidemic,2,3 and SA AGYW acquire HIV at twice the rate of and seroconvert on average 5 – 7 years earlier than male peers.3 As new infections continue to outpace access to and availability of PrEP and ART, primary prevention remains the most viable strategy to stem new transmissions.1,4,5 SA efforts to prevent HIV transmission in youth focus mostly on individual-level behavior change,6-8 but AGYW's persistent HIV disparities are explained by broad social and structural inequities that shape and constrain HIV-risk behaviors.9-14 Comprehensive HIV prevention packages that are integrated, synergistic, and tailored to the local epidemiology and cultural context are likely to achieve and sustain maximum reductions in HIV-risk.15-22 Female caregivers (FC) are an untapped resource in the HIV prevention toolbox23,24 and offer a novel opportunity to strengthen AGYW prevention efforts. AGYW may also be change agents for their FC who want to be positive role models for AGYW, and thus, adopt HIV prevention behaviors, including HTC and PrEP. Guided by an ecological framework, our highly experienced multidisciplinary team will adapt (phase 1/UG3) and evaluate the effectiveness and cost-effectiveness of (phase 2/UH3) IMARA, a multilevel, innovative, family-based HIV prevention program that targets individual, social, and structural drivers of risk to decrease HIV and STI incident infections, reduce risky sexual behavior, and increase HTC and PrEP uptake (where appropriate) in AGYW and FC. IMARA demonstrated a 45% reduction in incident STI at 12-month follow-up among black 14-18 year-old girls in the US, and increased HIV testing in FC. Pilot data with 71 AGYW and FC at the Desmond Tutu HIV Foundation (DTHF; study site) confirm feasibility and acceptability of IMARA for the South African context. This study will be integrated into the adolescent-friendly services at DTHF in the Western Cape metropolitan area facilitating sustainability if effective. Using the ADAPT-ITT model, we will systematically tailor IMARA for the SA context and then conduct a 2-arm RCT with 300 15-19 year-old AGYW and FC. FC and AGYW will complete baseline, 6-, and 12-month assessments, including testing for 3 STI. We will offer HTC and PrEP at each assessment and track uptake and linkage to care. AGYW and FC who test positive for a STI and/or HIV will receive free treatment at DTHF. We will collect data to determine the costs of IMARA. Analyses will compare AGYW and FC across the intervention and control programs on sexual risk taking, STI and HIV incidence, PrEP and HTC uptake, and theoretical mediators. The study answers an urgent need to evaluate the effectiveness and cost-effectiveness of combination HIV prevention packages for AGYW to achieve an AIDS-free generation.