To examine potential associations of the Glu298Asp polymorphism in the coding region of the endothelial nitric oxide synthase (eNOS) gene with susceptibility to and clinical expression of systemic lupus erythematosus (SLE). One hundred thirteen consecutive patients of European ancestry with diagnosis of SLE, satisfying the American College of Rheumatology criteria, from the outpatient clinic of the Serviço de Reumatologia of the Hospital de Clínicas de Porto Alegre, and 206 healthy controls from the same geographic area were genotyped by polymerase chain reaction for the Glu298Asp polymorphism in the coding region of the eNOS gene. Clinical, demographic, and laboratorial data were collected. Clinical manifestations of SLE and related diseases were evaluated for the association with specific genotypes. The allelic and genotypic distribution of the Glu298Asp did not differ significantly between SLE patients and controls. We found no association of the polymorphism with lupus nephritis, antiphospholipid syndrome, cardiovascular disease (CVD), and risk factors to CVD. The presented results in this study do not provide support for a major role of eNOS Glu298Asp neither in the susceptibility for SLE or clinical manifestations, although there was low statistical power for the latter evaluation.