Injection drug use is an important factor in the spread of HIV infection, and strategies to enhance adherence to HIV therapeutics are critically important to controlling viral transmission and improving clinical outcomes. To this end, the authors sought (1) to enhance adherence to highly active antiretroviral therapy (HAART) among methadone-maintained injection drug users (IDUs) using modified directly observed therapy (MDOT), and (2) to define interactions between methadone and HAART and the potential contribution of drug interactions to adherence and HIV outcomes in this population. Adherence was explored here through a pilot, unblinded, 24-week study in a methadone maintenance program in which simplified HAART (efavirenz and didanosine [one daily] and a second nucleoside [twice daily]) was administered 6 days/week by clinic staff to HIV-infected IDUs (n = 5) with their methadone. Evening doses of riboflavin-tagged nucleoside and one full day of medication weekly were given as take home doses. As a result of HAART administration, four of five participants with mean viral load at baseline of 10(5) copies/ml had undetectable viral load by 8 weeks of treatment (p = .043). Methadone area under the curve (AUC) decreased by 55% (p = .007) within 2 weeks of initiating this HAART regimen, and a mean methadone dose increase of 52% was required. The authors conclude that MDOT is a promising intervention for the treatment of IDUs with HIV disease, though significant drug interactions must be monitored for carefully and rapidly addressed.