HIV has reached epidemic proportions among African Americans in the USA but certain urban contexts appear to experience a disproportionate disease burden. Geographic information systems mapping in Philadelphia, indicates increased HIV incidence and prevalence in predominantly Black census tracts, with drastic differences across adjacent communities. What factors shape these geographic HIV disparities among Black Philadelphians? This descriptive qualitative study was designed to refine and validate a conceptual model developed to better understand multi-level determinants of HIV-related risk among Black Philadelphians. We used an expanded ecological approach to elicit reflective perceptions among administrators, direct service providers, and community members about individual, social, and structural factors that interact to protect against or increase the risk for acquiring HIV within their community. Gender equity, social capital, and positive cultural mores (e.g., monogamy, abstinence) were seen as the main protective factors. Historical negative contributory influences of racial residential segregation, poverty, and incarceration were the most salient risk factors. This study was a critical next step toward initiating theory-based, multi-level community-based HIV prevention initiatives.