A better understanding of the social-structural factors that influence HIV vulnerability is crucial to achieve the goal of ending the HIV epidemic by 2030. Given the role of neighborhoods in HIV outcomes, synthesis of findings from such research is key to inform efforts toward HIV eradication. We conducted a systematic review to examine the relationship between neighborhood-level factors (e.g., poverty) and HIV vulnerability (via sexual behaviors and substance use). We searched six electronic databases for studies published from January 1, 2007 through November 30, 2017 (PROSPERO CRD42018084384). We also mapped the studies’ geographic distribution to determine whether they aligned with high HIV prevalence areas and/or the “Ending the HIV Epidemic: A Plan for the United States”. Fifty-five articles met inclusion criteria. Neighborhood disadvantage, whether measured objectively or subjectively, is one of the most robust correlates of HIV vulnerability. Tests of associations more consistently documented a relationship between neighborhood-level factors and drug use than sexual risk behaviors. There was limited geographic distribution of the studies, with a paucity of research in several counties and states where HIV incidence/prevalence is a concern. Neighborhood influences on HIV vulnerability are the consequence of centuries-old laws, policies and practices that maintain racialized inequities (e.g., racial residential segregation, inequitable urban housing policies). We will not eradicate HIV without multi-level, neighborhood-based approaches to undo these injustices. Our findings inform future research, interventions and policies.