Women in the United States are increasingly affected by HIV/AIDS, most commonly through heterosexual contact. Engagement in HIV-related sexual risk behaviors has been associated with childhood sexual abuse, emotional distress or depression, substance abuse, violence, financial hardship, and self-worth. Together childhood sexual abuse, emotional distress, substance use, violence, and financial hardship have been hypothesized to represent a syndemic: a set of mutually reinforcing health and social problems that interact and impose an increased burden on vulnerable populations. To date, models of HIV-related syndemics have predominantly assessed the linear oradditive'relationships between syndemic constructs and outcomes (eg, engagement in HIV-related high risk behaviors). We applied system dynamics modeling to assess the simultaneous interdependencies among these constructs. Our work is organized into two parts. First, we used previously collected cohort data describing women with a history of HIV-related high-risk behaviors (including unprotected sex, sex with multiple partners, and sex work; n= 620) to evaluate hypothesized differences in HIV-related sexual self-care by reported history of childhood sexual abuse and HIV-status. Using baseline data, we conducted a replication study of Stall et al.'s (2003) previously identified additive methodology, which had suggested an incremental relationship between number of syndemic variables and level of HIV-related high-risk behaviors. Our findings supported outcomes of their prior statistical modeling. However, our analysis showed that several constructs were not significantly related HIV-related high-risk behaviors (eg, recent substance use and violent events). Second, we used system dynamics modeling to further examine feedback processes among the proposed syndemic constructs. Our model was informed by review of applicable research literature, qualitative input from members of the Bronx Community Research Review Board (BxCRRB), as well as results from the first part of this study. The final model demonstrates the causal influence of violent events and substance use on self-worth, emotional distress, and HIV-related high-risk behaviors. Self-worth was a central driver in all feedback processes, as it is well supported in the literature and was affirmed by the BxCRRB as imperative to the syndemic. Simulation output displays changes in these constructs over a hypothetical period of 104 weeks (2 years) for selected clinically relevant profiles of women with and at-risk for HIV in the Bronx. Overall, the system dynamics modeling fostered a critical understanding about patterns of interdependency among the syndemic variables that were not evident in the general linear modeling and enabled a more comprehensive exploration of applied syndemic theory.