AIDS is a major cause of preventable mortality in HIV-infected people who inject drugs (HIV-PWID). An observational study was conducted to examine trends in AIDS mortality and related factors among HIV-infected individuals who died between 2000 and 2015 at an urban hospital. Overall HIV-mortality was 6.5% (413/6307) with no changes over time (p 0.76). AIDS mortality dropped in HIV-PWID (p 0.02) although it represented 26.4% at the end of study period. Age (per one-year increase) [odds ratio (OR) 0.95], third study period (2010-2015) (OR 0.54), HIV-PWID on opioid agonist therapy (OAT) (OR 0.39), and HIV RNA suppression (OR 0.15) were associated with AIDS mortality. OAT was reported in 58.3% (161/276) and RNA suppression in 30.9% (85/276) of HIV-PWID. OAT non-retention was due to drop-outs [85.2% (98/115)] and rejection [14.8% (17/115)] in HIV-PWID. Therefore, additional strategies are required to improve OAT retention and HIV RNA suppression to continue reducing AIDS mortality.