Human immunodeficiency virus (HIV)-positive injection drug users (IDUs) are known to be at risk for multiple medical problems that may necessitate emergency department (ED) use; however, the relative contribution of HIV disease vs. injection-related complications has not been well described. Objectives We examined factors associated with ED use among a prospective cohort of HIV-positive IDUs in a Canadian setting. Methods We enrolled HIV-positive IDUs into a community-recruited prospective cohort study. We modeled factors associated with the time to first ED visit using Cox regression to determine factors independently associated with ED use. In sub-analyses, we examined ED diagnoses and subsequent hospital admission rates. Results Between December 5, 2005 and April 30, 2008, 428 HIV-positive IDUs were enrolled, among whom the cumulative incidence of ED use was 63.7% (95% confidence interval [CI] 59.1–68.3%) at 12 months after enrollment. Factors independently associated with time to first ED visit included: unstable housing (hazard ratio [HR] 1.5; 95% CI 1.1–2.0) and reporting being unable to obtain needed health care services (HR 2.2; 95% CI 1.2–4.1), whereas CD4 count and viral load were non-significant. Skin and soft tissue infections accounted for the greatest proportion of ED visits (17%). Of the 2461 visits to the ED, 419 (17%) were admitted to the hospital. Conclusions High rates of ED use were observed among HIV-positive IDUs, a behavior that was predicted by unstable housing and limited access to primary care. Factors other than HIV infection seem to be driving ED use among this population in the post-highly active antiretroviral therapy era.