In the present study, we sought to identify rates, causes, and predictors of death among male and female injection drug users (IDUs) in Vancouver, British Columbia, Canada, during a period of expanded public health interventions. Data from prospective cohorts of IDUs in Vancouver were linked to the provincial database of vital statistics to ascertain rates and causes of death between 1996 and 2011. Mortality rates were analyzed using Poisson regression and indirect standardization. Predictors of mortality were identified using multivariable Cox regression models stratified by sex. Among the 2,317 participants, 794 (34.3%) of whom were women, there were 483 deaths during follow-up, with a rate of 32.1 (95% confidence interval (CI): 29.3, 35.0) deaths per 1,000 person-years. Standardized mortality ratios were 7.28 (95% CI: 6.50, 8.14) for men and 15.56 (95% CI: 13.31, 18.07) for women. During the study period, mortality rates related to infection with human immunodeficiency virus (HIV) declined among men but remained stable among women. In multivariable analyses, HIV seropositivity was independently associated with mortality in both sexes (all P < 0.05). The excess mortality burden among IDUs in our cohorts was primarily attributable to HIV infection; compared with men, women remained at higher risk of HIV-related mortality, indicating a need for sex-specific interventions to reduce mortality among female IDUs in this setting.