Background: Nearly a quarter of the 1.1 million individuals with HIV in the United States are women. Racial and ethnic minority women in the Southern United States are disproportionately impacted. Reproductive-age women with HIV are prone to poor HIV outcomes but remain underrepresented in HIV research. We will answer contemporary questions related to the health outcomes in this population by enrolling a prospective cohort of reproductive-age women with and without HIV in the Southern United States. Objective: The Study of Treatment and Reproductive Outcomes (STAR) will enroll and retain 2000 reproductive-age women with and without HIV. The STAR will leverage the infrastructure of the US-based Multicenter AIDS Cohort Study (MACS)/Women's Interagency HIV Study (WIHS) Combined Cohort Study, comprising the WIHS (a cohort of women with and at risk for HIV, which began in 1993), and the MACS (a cohort of gay and bisexual men with and at risk for HIV, which began in 1984). Although the advancing age of the participants enrolled in the MACS/WIHS Combined Cohort Study provides an opportunity to address the questions related to HIV and aging, the research questions pertinent to the reproductive years must also be addressed. The STAR will conduct high-priority scientific research in key areas with the overall aim of addressing the unique needs of reproductive-age women with HIV. Methods: The STAR is a prospective, observational cohort study that will be conducted at 6 sites in the United States-Atlanta, Georgia; Birmingham, Alabama; Jackson, Mississippi; Chapel Hill, North Carolina; Miami, Florida; and Washington, District of Columbia. Visits will occur semiannually for 2 years, with additional visits for up to 5 years. At each visit, the participating women will complete a structured interview for collecting key demographic, psychosocial, and clinical variables, and undergo biospecimen collection for laboratory testing and repositing (blood, urine, hair, vaginal, anal, and oral specimens). Pregnant women and infants will undergo additional study assessments. The initial scientific focus of the STAR is to understand the roles of key social determinants of health, depression, reproductive health, and oral health on HIV and pregnancy outcomes across the reproductive life span. Results: Enrollment in the STAR commenced in February 2021 and is ongoing. Conclusions: Through in-depth, longitudinal data and biospecimen collection, the newly initiated STAR cohort will create a platform to answer scientific questions regarding reproductive-age women with and without HIV. STAR will be uniquely positioned to enable investigators to conduct high-impact research relevant to this population. Building on the legacy of the MACS and WIHS cohorts, the STAR is designed to foster multidisciplinary collaborations to galvanize scientific discoveries to improve the health of reproductive-age women with HIV and ameliorate the effects of the HIV epidemic in this population in the United States.