The aim of the present study was to compare the effect of PIO (pioglitazone) or GLIM (glimepiride) on erythrocyte deformability in T2DM (Type 2 diabetes mellitus). The study covered 23 metformin-treated T2DM patients with an HbA1c (glycated haemoglobin) >6.5%. Patients were randomized to receive either PIO (15 mg, twice a day) or GLIM (1 mg, twice a day) in combination with metformin (850 mg, twice a day) for 6 months. Blood samples were taken for the measurement of fasting glucose, HbA1c, fasting insulin, intact proinsulin, adiponectin and Hct (haematocrit). In addition, the erythrocyte EI (elongation index) was measured using laser diffractoscopy. Both treatments significantly improved HbA1c levels (PIO, −0.9±1.1%; GLIM, −0.6±0.4%; both P<0.05) and resulted in comparable HbA1c levels after 6 months (PIO, 6.5±1.2%; GLIM, 6.2±0.4%) Treatment with PIO reduced fasting insulin levels (−8.7±15.8 milli-units/l; P=0.098), intact proinsulin levels (−11.8±9.5 pmol/l; P<0.05) and Hct (−1.3±2.3%; P=0.09), whereas adiponectin levels increased (8.2±4.9 μg/ml; P<0.05). No significant change in these parameters was observed during GLIM treatment. PIO improved the EI, resulting in a significant increase in EI at all physiological shear stress ranges (0.6–6.0 Pa; P<0.05). The improvement in EI correlated with the increase in adiponectin levels (r=0.74; P<0.001), and inversely with intact proinsulin levels (r=−0.47; P<0.05). This is the first study showing an improvement in EI during treatment with PIO, which was associated with an increase in adiponectin and a decrease in intact proinsulin levels, but independent of glycaemic control.