High levels of adherence to antiretroviral medications are required to maximize therapeutic benefits and viral suppression. Injecting drug use (IDU) is associated with decreased adherence levels, unstable living conditions and mental health problems. Despite the prevalence of these nonadherence risks in HIV-positive IDUs, little study has been conducted to date to assess the impact of homelessness and psychological distress on adherence in this population. The present study evaluated the effects of housing status (homeless/marginally housed versus nonhomeless) and psychological distress, measured via depression, anxiety and perceived stress, on self-reported adherence in 58 HIV-positive IDUs. Results from this study indicated that homeless/marginally housed HIV-positive IDUs reported higher levels of anxiety and perceived stress than their nonhomeless counterparts. The groups reported similar levels of depression. However, only depression was significantly related to adherence. Housing status, drug or alcohol use, and other demographic variables including gender, race/ethnicity, and years of education, were not associated with adherence. This study also found a relatively high rate of adherence in homeless/marginally housed IDUs with more than half (63%) reporting perfect (100%) adherence levels. Findings from this study suggest that when evaluating patient readiness for antiretroviral medications, current housing may not need to be the primary concern. Rather, depression may be a more potent indicator of nonadherence than homelessness for HIV-positive IDUs.