This 6-month randomized controlled trial evaluated the impact on quality of life (QOL) of a medication reminder device for patients with HIV. Patients were eligible if they had taken three or fewer highly active antiretroviral therapy (HAART) regimens or were treatment naïve. The intervention group received the Disease Management Assistance System (DMAS), a prompting device that verbally reminds patients at medication times and electronically records doses, and a monthly 30 minute adherence educational session. Controls received education only. QOL was measured at baseline and 6 months using the Centers for Epidemiologic Studies Depression Scale (CES-D), Instrumental Activities of Daily Living (IADLs), and the Medical Outcomes Study HIV Health Survey (MOS-HIV). At baseline, 62 patients completed surveys (31 control, 31 DMAS); at month 6, 48 patients completed surveys (23 control, 25 DMAS). At month 6, controls had improved QOL scores for CES-D, IADLs, physical health, general health, pain, QOL, and role functioning, while participants in the DMAS arm had some deterioration in QOL scores. These differences persisted after controlling for demographics, baseline CD4, and adherence. DMAS was associated with improved adherence but decreased QOL.