Insulin resistance is mainly present in skeletal muscle in non-obese patients with myotonic dystrophy. Thiazolidinediones are reported to reduce insulin resistance in these patients. However, the effects of pioglitazone in overweight patients with myotonic dystrophy and type 2 diabetes mellitus have not been established. Here, we evaluated the effect of pioglitazone in two poorly-controlled over-weight diabetic patients with myotonic dystrophy. Case 1 was a 41- year-old women (BMI 27.8 kg/m(2)) with myotonic dystrophy and type 2 diabetes had been treated with 3 mg/day glimepiride and 500 mg/day metformin, but the treatment failed to achieve good glycemic control (HbA(1C) 11.8 %). Following admission to the hospital, she was treated with low-dose insulin and 30 mg/day pioglitazone. At 10 days after initiation of therapy, glycemic control was improved, serum IL-6 and hs-CRP decreased, and adiponectin level increased rapidly. Case 2 was a 47-year-old women (BMI 29.2 kg/m(2)) with myotonic dystrophy and type 2 diabetes mellitus had been treated with insulin without successful glycemic control (HbA(1C) 10.3 %). After admission, she was treated with 15 mg/day pioglitazone. This improved glycemic control, reduced daily insulin requirement, decreased IL-6 and hs-CRP levels rapidly and increased adiponectin level at 10 days after initiation of therapy. In both cases, pioglitazone rapidly improved glycemic control, enhanced adiponectin production, and reduced inflammatory cytokines. These results suggest that pioglitazone may be suitable for these patients.