Despite the advent of effective antiretroviral therapy (ART), HIV-seropositive injection drug users (IDU) continue to suffer from elevated levels of morbidity and mortality. Evidence is needed to identify social- and structural-level barriers to effective ART. We investigated the impact of homelessness on plasma HIV RNA response among illicit drug users initiating ART in a setting with free and universal access to HIV care. We accessed data from a long-running prospective cohort of community-recruited IDU linked to comprehensive HIV clinical monitoring and ART dispensation records. Using Cox proportional hazards with recurrent events modeling, we estimated the independent effect of homelessness on time to plasma HIV viral load suppression. Between May 1996 and September 2009, 247 antiretroviral naïve individuals initiated ART and contributed 1755 person-years of follow-up. Among these individuals, the incidence density of plasma HIV RNA suppression less than 500 copies/mm(3) was 56.7 (95% confidence interval [CI]: 46.9-66.0) per 100 person-years. In unadjusted analyses, homelessness was strongly associated with lower rates suppression (hazard ratio = 0.56, 95% CI: 0.40-0.78, p = 0.001), however, after adjustment for adherence this association was no longer significant (adjusted hazard ratio = 0.79, 95% CI: 0.56-1.11, p = 0.177). Homelessness poses a significant structural barrier to effective HIV treatment. However, since this relationship appears to be mediated by lower levels of ART adherence, interventions to improve adherence among members of this vulnerable population are needed.