Novel approaches are needed to improve adherence to combination antiretroviral therapy. Nonadherence can lead to reduced drug levels and inadequate viral suppression, which accelerates drug resistance. Thus nonadherence in the first few months of primary HIV infection can limit therapeutic options for an individual years later. Barriers to optimal treatment adherence in patients with early HIV infection include complex treatment regimens which disrupt daily routines, drug intolerance, and concomitant illness including depression. Directly observed therapy has been successful in improving overall effectiveness of antituberculosis therapy and may be a useful strategy in HIV-infected patients.