High levels of adherence to highly active antiretroviral therapy (HAART) are essential for virologic suppression and longer survival in patients with HIV. We examined the effects of substance abuse treatment, current versus former substance use, and hazardous/binge drinking on adherence to HAART. During 2003, 659 HIV patients on HAART in primary care were interviewed. Adherence was defined as > or =95% adherence to all antiretroviral medications. Current substance users used illicit drugs and/or hazardous/binge drinking within the past six months, while former users had not used substances for at least six months. Logistic regression analyses of adherence to HAART included demographic, clinical and substance abuse variables. Sixty-seven percent of the sample reported 95% adherence or greater. However, current users (60%) were significantly less likely to be adherent than former (68%) or never users (77%). In multivariate analysis, former users in substance abuse treatment were as adherent to HAART as never users (Adjusted Odds Ratio (AOR)=0.82; p>0.5). In contrast, former users who had not received recent substance abuse treatment were significantly less adherent than never users (AOR=0.61; p=0.05). Current substance users were significantly less adherent than never users, regardless of substance abuse treatment (p<0.01). Substance abuse treatment interacts with current versus former drug use status to affect adherence to HAART. Substance abuse treatment may improve HAART adherence for former substance users.