We investigated whether tumor necrosis factor (TNF) microsatellite polymorphisms are associated with sex and age at disease onset in rheumatoid arthritis (RA). A case-control study was used to compare the frequencies of TNF microsatellite alleles in 181 Caucasian RA cases and 251 controls. TNF microsatellite genotyping was performed using fluorescent based polymerase chain reaction (PCR) techniques and HLA-DR typing using PCR based sequence specific oligonucleotide probing. The association of TNF microsatellite alleles a6, b5, and d4 with RA was confirmed. These polymorphisms were more frequent in female patients. Male patients with RA with young age at onset had a different TNF microsatellite profile, TNFa2, b1, and c2 being the most frequent. TNF microsatellite polymorphisms are different in male and female patients with RA. This difference was more obvious in patients stratified according to age at onset. Sex and age at onset should be considered in studies of genetic factors in RA.