The human major histocompatibility complex (MHC) contains two closely related genes (TAP) that encode a family of transporter proteins. It is known that the TAP genes, like other MHC (class I and class II) genes, are polymorphic. In this study we investigated the polymorphisms in the ATP-binding domain of the TAP2 gene and examined the relationship of these polymorphisms to susceptibility to rheumatoid arthritis (RA). On the basis of the distribution of polymorphisms in these genes, three TAP2 alleles could be identified in homozygous typing cell lines, RA patients and normal subjects: TAP2*0101-1693.G, TAP2*0101-1693.A and TAP2*0201-1693.G. The prevalence of the variant (nucleotide A at position 1693), and thus also of the TAP2*0101-1693.A allele, was significantly (p < 0.006, RR = 4.25) higher in RA patients (35.3%) than in normal controls (11.4%). In addition, the TAP2*0101-1693.A allele showed significant (r = 0.45, p < 0.0003) association with HLA-DR4 only in RA patients and the prevalence of both TAP2*0101-1693.A and DR4 genes gave the highest relative risk (RR = 19.21, p < 0.0002) for RA. These data suggest that the MHC region containing both class II and TAP genes confers the strongest susceptibility to RA, with the highest RR value reported so far. It is likely that the genetic variability in the putative peptide transporter could also be implicated in immunological disorders associated with MHC.