Improving medication nonadherence in HIV-infected patients with concomitant psychiatric issues remains a challenging therapeutic dilemma. One strategy may be to use a short course of modified directly observed therapy combined with therapeutic drug monitoring as an adherence intervention. Individual drug pharmacokinetics could be evaluated while the increased visit frequency is an opportunity to provide additional patient training and psychosocial support. We report our experience with a 43-year-old woman with severe depressive symptoms and persistent virologic failure despite appropriate therapy. Although the intervention was well-received by the patient, improvements in medication adherence behaviors waned over time. It should be recognized that not all patients are capable of achieving lifelong medication adherence and may benefit from continued supervised therapy.