Nitric oxide (NO) was found to modulate uric acid production through its influence on xanthine oxidase activity, and a close circadian relationship of serum uric acid (SUA) and NO was reported. Studies also revealed that serum NO activity could be determined by endothelial constitutive nitric oxide synthase gene (ecNOS) polymorphism. This study was designed to investigate whether SUA could be influenced by a 27-bp repeat polymorphism in intron 4 of ecNOS gene. A total of 398 nondiabetic subjects and 800 patients with type 2 diabetes were studied. The ecNOS gene intron 4 polymorphism was determined by polymerase chain reaction (PCR). The mean SUA level of patients having type 2 diabetes was significantly lower than that of control subjects (6.1 +/- 1.8 mg/dL v 6.6 +/- 1.8 mg/dL, P<.001); and the mean SUA level of diabetic patients with ecNOS ab/aa genotypes was lower than that of patients with bb genotype (5.7 +/- 1.6 mg/dL v 6.2 +/- 1.8 mg/dL, P=.008). When subgrouped by gender, the SUA of female diabetic subjects was found to be significantly associated with ecNOS genotype. Using Pearson's correlation analysis and multiple linear regression analysis, ecNOS genotype was noticed to be an independent factor in contributing to SUA variability in female diabetic patients. Our results suggest that SUA levels may be associated with NO activity and can be genetically predetermined.