To investigate the influence of the S447X variant in lipoprotein lipase (LPL) gene on the response rate to therapy with the thiazolidinedione pioglitazone. A total of 113 diabetic patients were treated with pioglitazone 30 mg for 10 weeks. Response to the pioglitazone treatment was defined by either a >10% relative reduction in fasting blood glucose (FBG) or a more than 1% decrease in glycosylated haemoglobin (HbA1c) values after 10 weeks of pioglitazone treatment. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism method. Using the criteria >10% relative reduction in FBG after 10 weeks of pioglitaone treatment, responder frequency to pioglitazone treatment in S447S genotype group is significantly higher than S447X genotype group. Meanwhile, the S447X genotype conferred a statistically significant 0.538-fold reduction in response rate to pioglitazone treatment relative to the S447S genotype. Moreover, pioglitazone treatment has significantly beneficial effects on serum lipid profile and blood pressure in S447S genotype carriers. The S447X variant in LPL gene may be a cause for therapy modification by pioglitazone.