Tumor necrosis factor (TNF) is involved in the pathogenesis of systemic lupus erythematosus (SLE), but the role of TNF polymorphisms in SLE susceptibility remains unclear. Previous studies in different populations report an inconsistent association of the TNF-alpha -308A allele with SLE, sometimes depending on the presence of HLA-DR3. We examined the association of polymorphisms in TNF-alpha (-308G/A, -238G/A) and TNFbeta (+252A/G) in a population-based study of SLE in the southeastern United States and considered TNF-SLE associations with respect to HLA-DR3 and DR2 and the interleukin (IL)-1alpha -889C/T polymorphism, previously linked to SLE in this population. Genotypes were analyzed for 230 recently diagnosed SLE patients who met American College of Rheumatology classification criteria and 276 age- and sex-matched controls, randomly selected from driver's license registries. Carriage of the TNF-alpha -308A allele was significantly associated with SLE in Caucasians (OR = 2.3; 95% CI 1.4, 3.9), but not African Americans. Analyses stratified by IL-1alpha -889 genotypes (C/C vs C/T or T/T) revealed independent associations of SLE with TNF-alpha -308A or HLA-DR2 and DR3. This reflected a significant interaction of TNF and IL-1 genotypes in Caucasians, and yielded a strong association (OR = 8.0, p < 0.00001) for the combined "HLA-DR3, TNF-alpha -308A, IL-1alpha -889C/C" genotype. These findings provide evidence of cytokine gene epistasis in SLE susceptibility.