Nuclear factor (NF)-kappaB plays an important role in inflammatory diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A functional insertion/deletion polymorphism (-94ins/delATTG) has been identified in the promoter of the NFKB1 gene. In addition, a polymorphic dinucleotide repeat (CA) has been identified in proximity to the coding region of the human NFKB1 gene. The aim of the present study was to investigate the influence of both the -94ins/delATTG and the (CA) microsatellite NFKB1 polymorphisms in the susceptibility/severity of RA and SLE. We analyzed the distribution of -94ins/delATTG and the multiallelic (CA)(n) repeat in 272 RA patients, 181 SLE patients, and 264 healthy controls from Southern Spain, in both cases using a polymerase chain reaction-fluorescent method. No statistically significant difference in the distribution of the -94delATTG NFKB1 genotypes and alleles between RA patients, SLE patients, and control subjects was observed. Similarly, we found no statistically significant differences in the (CA)(n) microsatellite allele frequency between controls and RA patients or SLE patients. In addition, no association was found between the above mentioned NFKB1 polymorphisms with any of the demographic and clinical parameters tested either in RA or in SLE patients. From these results, it seems that the -94ins/delATTG and the (CA)(n) repeat of NFKB1 gene may not play a relevant role in RA and/or SLE in our population.