Multiple genetic factors contribute to susceptibility to rheumatoid arthritis (RA). The extent of variability in disease presentation in RA may be related to genetic heterogeneity. In this study we investigated the association of the TNF gene polymorphism at position +489 with susceptibility to and severity of RA. Analysis of the frequency of the +489 A and G alleles in a group of 293 consecutive RA patients and 138 healthy controls revealed a significant decrease of the A allele. The +489 GA patients had a 3.9 times decreased chance of having erosive disease than +489 GG patients. These results were confirmed in a prospective study using a cohort of 112 patients who were followed for 12 years. The progression rate of the erosion score over 12 years expressed as Sharp score for X-rays of hands and feet was 3.4 per year for the GA-genotyped patients and 12.1 for the GG-genotyped patients. These associations were independent of rheumatoid factor and HLA-shared epitope positivity. In conclusion, these data suggest that the intron TNF +489 polymorphism is associated with susceptibility to and disease severity of RA independently of HLA-shared epitope-positive alleles.