OBJECTIVES: We sought to examine whether there were differential rates of HIV incidence among Aboriginal and non-Aboriginal injection drug users in a Canadian setting. METHODS: Data were derived from 2 prospective cohort studies of injection drug users in Vancouver, British Columbia. Using the Kaplan-Meier method and Cox proportional hazards regression, we compared HIV incidence among Aboriginal and non-Aboriginal participants. RESULTS: Overall, 2496 individuals were recruited between May 1996 and December 2005. Compared with that of non-Aboriginal persons, the baseline HIV prevalence was higher among Aboriginal persons (16.0% vs 25.1%; P<.001). Among participants who were HIV negative at baseline, the cumulative HIV incidence at 48 months was higher among Aboriginal persons (18.5% vs 9.5%; P<.001). In multivariate analyses, Aboriginal ethnicity was independently associated with elevated HIV incidence (relative hazard=1.59; 95% confidence interval=1.12, 2.26; P=.009). CONCLUSIONS: Aboriginal persons in Vancouver had a significantly elevated burden of HIV infection, which calls for a culturally sensitive and evidence-based response. Policymakers in other settings with at-risk Aboriginal populations should seek to avert similar public health emergencies by being proactive with evidence-based HIV-prevention programs.