OBJECTIVE: We sought to assess health-related quality of life (HRQOL) in patients with type 2 diabetes treated with insulin glargine or rosiglitazone as add-on therapy to sulfonylurea plus metformin. RESEARCH DESIGN AND METHODS: HRQOL was evaluated in 217 subjects uncontrolled with sulfonylurea plus metformin, enrolled in a 24-week, multicenter, randomized, open-label, parallel-group trial of add-on insulin glargine versus rosiglitazone. A 40-item, self-administered questionnaire at baseline and at weeks 2, 6, 12, 18, and 24 was given, including the 34-item Diabetes Symptom Checklist-Revised (DSC-R), a 5-item mental health scale from the 36-item Short-Form Health Survey (SF-36), and a single-item health rating from the SF-36. These assessments do not specify route of therapy. RESULTS: Both treatment groups showed similar improvements in glycemic control from baseline to week 24 (change in A1C: -1.66% in the insulin glargine group, -1.51% in the rosiglitazone group, P = 0.1446). Both groups also showed improvement in HRQOL, although subjects treated with insulin glargine experienced significantly greater improvements compared with rosiglitazone in the DSC-R total symptom score (P = 0.005), total symptom distress score (P = 0.03), individual domain scores for mood symptoms (P = 0.007), ophthalmologic symptoms (P = 0.007), ophthalmologic distress (P = 0.013), fatigue distress (P = 0.033), and SF-36 perception of general health (P = 0.047). CONCLUSIONS: Although addition of insulin glargine and rosiglitazone achieved comparable improvements in glycemic control, insulin glargine was associated with greater improvements in HRQOL, indicating that other factors (e.g., safety profile and nonglycemic actions) may further enhance HRQOL in patients with type 2 diabetes.