Although rheumatoid arthritis has long been associated with HLA shared epitopes, a systematic search for epitopes has never been reported. We have developed a computer program that can analyze large HLA data sets and detect all shared epitopes comprising from one to five amino acids. We analyzed high resolution data from the International Histocompatibility Working Group, which included 639 subjects with rheumatoid arthritis and 429 controls, for all combinations of up to five amino acids among HLA-DRB1 positions 9-86. We compared this analysis with a traditional allele analysis and the prevalence of the QRAA epitope. Statistical significance was determined using a Chi-square analysis with a Bonferroni correction. The allele analysis identified three HLA alleles that were positively associated with RA, DRB1*0401 (p=2x10-9), *0404 (p=0.006) and *0405 (p=3x10-5) and five alleles that were resistant, DRB1*0701 (p=0.007), *0801 (p=0.037), *1101 (p=0.037), *1301 (p=0.04) and *1302 (p=0.004). DRB1*0101 (p=0.24) and *0102 (p=0.421) were not associated with RA in this data set. The single amino acid analysis identified V11 (p=10-16), H13 (p=10-16), Y37 (p=10-5), L67 (p=3x10-9), Q70 (p=0.0001) and A74 (p=0.0007) as RA-susceptibility markers. In addition, S11 (p=4x10-7), S13 (p=2x10-6), I67 (p=3x10-7) and D70 (p=5x10-9) were RA-resistance markers. The combination of these positions yielded a VHYLA11,13,37,67,74epitope that was more strongly associated with RA (p=4x10-22) than QRAA70,71,73,74 (p=9x10-10) or QKAA70,71,73,74 (p=3x10-10). VHYLA is associated with DRB1*0401,*0404,*0405,*0408, *0409 and *0410, but not with DRB1*01 alleles, consistent with the allele analysis in this data set.