Genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) and nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase p22phox are linked with the expression and/or progression of vascular disease. We hypothesized that these polymorphisms may influence the development and/or progression of systemic lupus erythematosus (SLE), given their linkage with vascular disease. DNA from patients with SLE (n = 90) and their age- and sex-matched controls (n = 86) from The Second Xiangya Hospital of Central South University was assessed for eNOS and NADPH oxidase p22phox polymorphisms. These polymorphisms were examined by restriction fragment length polymorphism-polymerase chain reaction. The allele frequency of the NADPH oxidase p22phox gene C242T polymorphisms significantly varied between the SLE patients and the controls. We found no association of the eNOS polymorphism with the development of renal disease. These results indicated that the etiology of patients with SLE is associated with NADPH oxidase p22phox gene C242T polymorphisms. There was no significant increased risk of SLE associated with eNOS polymorphisms in the Chinese population.