This study was performed to examine the efficacy and safety of the rapid- and short-acting insulinotropic SUR ligand mitiglinide given as add-on therapy for 52 weeks in type 2 diabetic patients whose blood glucose was insufficiently controlled by pioglitazone monotherapy. Type 2 diabetic patients aged ≥ 20 years with postprandial plasma glucose (PPG1 or 2) ≥ 200 mg/dL and glycated hemoglobin (HbA_1C) 6.5–<9.0% despite receiving pioglitazone 15–45 mg/day were additionally treated with concomitant mitiglinide 10 mg tid p.o. for a total treatment period of 52 weeks. In 171 patients recruited, HbA_1C was significantly reduced from 7.64 ± 0.77% at baseline to 6.84 ± 0.73%, 6.64 ± 0.64%, 6.67 ± 0.57% and 6.81 ± 0.65% at weeks 16, 28, 40, and 52, respectively. Over half the patients achieved HbA_1C target of <7.0%, and one third <6.5%. Significant reductions in fasting plasma glucose (FPG) and PPG 1 and 2 hours after a meal versus baseline were noted at all time-points evaluated. The most frequently noted adverse reactions were hypoglycemic symptoms, weight gain, and peripheral edema (all mild). In type 2 diabetic patients combination therapy with mitiglinide and pioglitazone exerted significant long-term improvements in HbA_1C, FPG, and PPG and was well tolerated. This drug combination therapy is a promising means of alleviating insufficient pancreatic insulin secretion and insulin resistance.