To determine the total burden of illicit drug overdose mortality over the study period in the province of British Columbia and investigate possible population-level determinants by estimating rates among subgroups including First Nations individuals. Review of coroner case files. The province of British Columbia, Canada. Individuals dying from an illicit drug overdose between 2001 and 2005. Age-adjusted mortality rates, standardized mortality ratios (SMR) and years of potential life lost (YPLL), stratified by major population groups. Over the study period, 909 individuals died from illicit drug overdoses, including 104 (11.4%) First Nations individuals. Compared to the general population, First Nations males and females suffered from substantially elevated SMR and YPLL. In a multivariate logistic regression analysis, First Nations deaths were significantly more likely to be among women, related to injection drug use and to have occurred in the Downtown Eastside area of Vancouver, the local epicentre of human immunodeficiency virus infection and open drug use (all P< 0.05). This report found highly elevated overdose death rates and levels of premature mortality among First Nations Canadians in British Columbia compared to the general population. While previously unidentified, these findings are consistent with the poorer population health profile of First Nations Canadians. Although further research is needed to identify the causes of the elevated death rates, our findings support increased availability of evidence-based overdose prevention measures. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.