Injection drug users who continue to use drugs may not respond to highly active antiretroviral therapy (HAART) as well as other HIV-infected individuals, even after adjusting for a reliable measure of adherence. We therefore compared the virologic response among participants in a population-based HIV/AIDS Drug Treatment Program in British Columbia, Canada, by injection drug use activity. Participants who were HIV infected and naive to antiretroviral therapy and who were prescribed antiretroviral treatment between August 1996 and December 2000 were eligible for this study. They were classified as current, former, or non-injection drug users. The main outcome was having two consecutive HIV-1 RNA levels less than 500 copies/mL. We used logistic regression to adjust for baseline HIV-1 RNA, type of antiretroviral regimen (2 nucleosides + nonnucleoside reverse transcriptase inhibitor versus 2 nucleosides + protease inhibitor), duration of therapy (months), adherence (derived from refill compliance data), and age. A total of 578 participants were first prescribed HAART during the study period. Among them, 78 (13%) were current injection drug users, 96 (17%) were former injection drug users, and 404 (70%) never injected drugs. In the multivariable logistic regression, relative to non-drug users, current injection drug users were significantly less likely to suppress their HIV-1 RNA (adjusted OR [AOR] = 0.30, 95% CI: 0.13-0.67), and former injection drug users were not significantly different from non-drug users (AOR = 0.56, 95% CI: 0.24-1.34). There was a significant interaction between drug use and adherence. In the analyses stratified by drug use, the adherence of former and non-drug users was positively associated with HIV-1 RNA suppression (AOR = 1.33, 95% CI: 1.14-1.55), whereas for current drug users, it was not (AOR = 1.07, 95% CI: 0.87-1.33). Current injection drug users were less likely to achieve HIV-1 RNA suppression compared with non-drug users. Adherence as measured by pharmacy refill compliance was not a reliable measure in this subpopulation.