OBJECTIVE: To evaluate the safety and efficacy of methazolamide as a potential therapy for type 2 diabetes. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled study randomized 76 patients to oral methazolamide (40 mg b.i.d.) or placebo for 24 weeks. The primary efficacy end point for methazolamide treatment was a placebo-corrected reduction in HbA1c from baseline after 24 weeks (ΔHbA1c). RESULTS: Mean ± SD baseline HbA1c was 7.1 ± 0.7% (54 ± 5 mmol/mol; n = 37) and 7.4 ± 0.6% (57 ± 5 mmol/mol; n = 39) in the methazolamide and placebo groups, respectively. Methazolamide treatment was associated with a ΔHbA1c of -0.39% (95% CI -0.82, 0.04; P < 0.05) (-4.3 mmol/mol [-9.0, 0.4]), an increase in the proportion of patients achieving HbA1c ≤6.5% (48 mmol/mol) from 8 to 33%, a rapid reduction in alanine aminotransferase (∼10 units/L), and weight loss (2%) in metformin-cotreated patients. CONCLUSIONS: Methazolamide is the archetype for a new intervention in type 2 diabetes with clinical benefits beyond glucose control.