The major histocompatibility (MHC) genes including TNF-alpha, HSP70 and HLA genes have been associated with systemic lupus erythematosus (SLE) in several populations. In this study we analyze the polymorphism of TNF-alpha promoter in 51 Mexican Mestizo SLE patients and 55 ethnically-matched healthy controls by polymerase chain reaction methods. No statistically significant differences were observed in the TNF -308 allele and genotype distribution between patients and healthy controls. However, we found a significant increase in the TNF G/A -238 genotype and in the TNFA -238 allele frequencies in the SLE group when compared with healthy controls (Pc = 0.03, OR = 4.77 and Pc = 0.02, OR = 3.62, respectively). DRB1 analysis showed a similar distribution in patients and controls. Linkage disequilibrium was observed for five haplotypes: DRB1*1401-TNFA-238 (D = 0.84; D' = 1.0; P = 0.015); DRB1*0301-TNFA-238 (D = 1.38; D' = 0.41; P = 0.042); DRB1*1106-TNF2-308 (D = 0.9; D' = 1.0; P = 0.0006); DRB1*1104-TNF2-308 (D = 0.83; D' = 0.45; P = 0.02) and DRB1*1406-TNF2-308 (D = 0.83; D' = 0.45; P = 0.02). Our data suggest that the association between the TNF-alpha -238 polymorphism and SLE could play a major role in disease susceptibility.