To determine the various factors influencing glycemic response to pioglitazone monotherapy in newly diagnosed Asian Indian T2DM patients. Thirty T2DM patients (age 53.23 +/- 8.067 yrs, M: F ratio 14:16) were treated with pioglitazone for at least 14 weeks. Relationship between its glucose lowering effect and following patient parameters was studied: BMI, W:H ratio, HOMA-R, HOMA-beta and Pro12Ala polymorph of PPAR-gamma gene. Glycemic targets could be achieved in 20 (66.67%) subjects. All the parameters were comparable among responders and non-responders at the start of therapy. All the participants were homozygous for Pro allele of Pro12Ala polymorph of PPAR-gamma gene. There was a significant positive association between glycemic response to pioglitazone and W: H ratio (beta = 0.426, P = 0.034) and HOMA-R (beta = 0.563, P = 0.008). Primary pioglitazone failure cannot be explained on the basis of body fat and its distribution, insulin resistance and secretory function and Pro12Ala polymorph of PPAR-gamma gene. Among responders central obesity and high insulin resistance were associated with better glycemic response.