Background: Syndemic models have been used in previous studies exploring HIV-related outcomes; however, these models do not fully consider intersecting psychosocial (e.g., substance use, depressive symptoms) and structural factors (unstable housing, concentrated housing vacancy) that influence the lived experiences of women. Therefore, there is a need to explore the syndemic effects of psychosocial and structural factors on HIV risk behaviors to better explain the multilevel factors shaping HIV disparities among black women. Methods: This analysis uses baseline data (May 2009-August 2010) from non-Hispanic black women enrolled in the HIV Prevention Trials Network 064 Women's Seroincidence Study (HPTN 064) and the American Community Survey 5-year estimates from 2007 to 2011. Three parameterizations of syndemic factors were applied in this analysis a cumulative syndemic index, three syndemic groups reflecting the level of influence (psychosocial syndemic group, participant-level structural syndemic group, and a neighborhood-level structural syndemic group), and syndemic factor groups. Clustered mixed effects log-binomial analyses measured the relationship of each syndemic parameterization on HIV risk behaviors in 1,347 black women enrolled in HPTN 064. Results: A higher syndemic score was significantly associated with increased prevalence of unknown HIV status of the last male sex partner (adjusted prevalence ratio (aPR) = 1.07, 95% confidence interval or CI 1.04-1.10), involvement in exchange sex (aPR = 1.17, 95% CI: 1.14-1.20), and multiple sex partners (aPR = 1.07, 95% CI: 1.06-1.09) in the last 6 months. A dose-response relationship was observed between the number of syndemic groups and HIV risk behaviors, therefore, being in multiple syndemic groups was significantly associated with increased prevalence of reporting HIV risk behaviors compared with being in one syndemic group. In addition, being in all three syndemic groups was associated with increased prevalence of unknown HIV status of the last male sex partner (aPR = 1.67, 95% CI: 1.43-1.95) and multiple sex partners (aPR = 1.53, 95% CI: 1.36-1.72). Conclusions: Findings highlight syndemic factors influence the lived experiences of black women.