Interleukin-6 (IL-6) is a multifunctional cytokine with an important pathophysiological role in systemic lupus erythematosus (SLE). The polymorphism of the IL-6 gene promoter at position -174, which appears to influence the production of this cytokine, has been associated with susceptibility to some rheumatic diseases. The aim of this study is to investigate whether the IL-6 -174 G/C polymorphism associates with lupus susceptibility or affects disease characteristics in Portuguese patients with SLE. The association between -174 G/C and lupus diagnosis was studied in 115 adult SLE patients (95.7% females) and 152 healthy controls (94.7% females), all Caucasians. There were no significant differences in genotype or allele frequency between patients and controls. The -174 C/C genotype was independently associated with renal disease and the C allele with the presence of irreversible damage. The IL-6 gene promoter polymorphism at position -174 does not contribute to SLE susceptibility in Portuguese Caucasian patients but may predispose to specific manifestations of the disease.