OBJECTIVE: Five loci-the shared epitope (SE) of HLA--DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region--have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone. METHODS: We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci. RESULTS: Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93). CONCLUSIONS: This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.