PROJECT SUMMARY While HIV prevention strategies have improved and HIV incidence rates continue to decrease in the United States (US), a critical need remains to strengthen and advance prevention science where declines appear to have stalled, particularly among cisgender women of color. The most recent surveillance data from the Centers for Disease Control and Prevention demonstrate that as of 2019, about 7,000 of all new HIV diagnoses were identified among cisgender women (hereafter simply referred to as “women”). Traditional demographic and behavioral risk factors are insufficient to identify women who are vulnerable to HIV infection. Recent research on the use of risk algorithms to determine pre-exposure prophylaxis (PrEP) eligibility demonstrated poor predictive power for women in contrast to good predictive value among men who have sex with men. Identifying women who are vulnerable to HIV infection is crucial for the development and deployment of tailored prevention approaches. While the mode of HIV acquisition for women is well known, with heterosexual contact (85%) identified as the most frequent mode of HIV transmission among women, followed by 15% due to injection drug use, less is known about the social-ecological factors (e.g., community, network, geospatial, and policy factors) associated with HIV seroconversion. Broadly, several factors beyond individual behavior have been associated with increased risk for HIV acquisition among women in the US such as gender inequality, income, exposure to domestic and sexual violence, homelessness, and sex partner’s characteristics. Nonetheless, identifying the combination of characteristics that predict seroconversion among women and establish them as candidates for PrEP has been challenging. To overcome this gap and in response to RFA-AI-21-058, we propose to harness innovative digital methods to establish a knowledgebase for women living in the US who are behaviorally vulnerable to HIV. The knowledgebase will consist of a national cohort of 1,800 women from whom we will collect HIV and sexually transmitted infections (STIs) incidence data and social and sexual network data, paired with open-source big data to contextualize HIV risk among women vulnerable to HIV infection. Our study team has extensive experience in using digital approaches to recruit study participants (through electronic methods and geospatial analytics). Capitalizing on our expertise, we will use the developed knowledgebase to identify theoretically-driven correlates of HIV seroconversion, STI incidence, and predictors of PrEP uptake. Findings will increase our understanding of women’s vulnerabilities to HIV infection, enhance identification of PrEP eligibility, and inform interventions to decrease the incidence of HIV and STIs among women living in the US.