This study was undertaken to investigate geographic residence in Vancouver's Downtown Eastside (DTES), Canada's poorest urban neighborhood, as an environmental risk factor for HIV infection among a cohort of injection drug users. HIV incidence rates were examined using Kaplan-Meier methods, and Cox proportional hazards regression was used to determine independent risk factors for HIV seroconversion. After intensive multivariate adjustment, DTES residence remained an independent predictor of HIV seroconversion (relative hazard=2.0, 95% CI: 1.4-3.0, p<0.001). These findings indicate the need for a greater recognition among policy-makers of geographic location as a risk factor for HIV incidence in urban settings and the need for further research to determine why place contributes so greatly to HIV risk. The findings also mark a need for prevention interventions to be appropriately targeted towards high-risk neighborhoods.