The objective of this study was to investigate the association between the heparan sulfate proteoglycan (HSPG) gene G/T polymorphism and diabetic nephropathy in type 2 diabetes in Chinese. The HSPG gene polymorphism (G/T) was determined using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) in 290 Chinese type 2 diabetes mellitus patients comprising 77 cases without nephropathy and 213 cases with nephropathy with either proteinuria (163) or renal insufficiency (50) and a control group of 190 non-diabetics. A significant increase in the frequencies of the T allele and TT + TG genotype was observed in subjects with diabetic renal insufficiency as compared with diabetic subjects without nephropathy and those with diabetic proteinuria (for the T allele: Fisher's two-tailed exact p was 0.015 and 0.002, respectively; for the TT + TG genotype; both p values were < 0.001). Diabetic subjects without nephropathy and those with albuminuria carrying the T allele had odds ratios for the development of renal insufficiency of 1.92 (95% CI, 1.12-3.30) and 2.09 (95% CI, 1.29-3.38), respectively, as compared to non-carriers. The T allele of the HSPG gene BamHI polymorphism located in intron 6 may be a risk factor for the development of renal insufficiency in type 2 diabetes mellitus for Chinese.