In most ethnic groups genetic susceptibility to rheumatoid arthritis (RA) is associated with certain HLA-DRB1 alleles encoding a similar sequence motif called the 'shared epitope' (SE) spanning amino acid positions 70 to 74 in the third diversity region of the outermost domain of the HLA-DRB1 molecule. We examined the association of the SE and RA in 83 Colombian women with established RA and 90 healthy controls. The group HLA-DRB1*04 was associated with RA with respect to controls (47% vs 18%, respectively. OR: 4.1, 95%CI: 2.1-8.2, P < 0.001). HLA-DRB1 alleles carrying the SE QRRAA, but not those carrying QKRAA or RRRAA, were associated with disease (OR: 3.7, 95%CI: 1.73-7.83, P = 0.0009). This association was stronger among HLA-DRB1*04 carriers (OR: 23, 95%CI: 1.3-414, P = 0.002). In our population, the SE QRRAA expressed in DRB1*04 alleles appears critical in identifying women with increased susceptibility to RA.