The adult population (N = 227) of a Chippewa Indian reservation in central Minnesota is characterized by a high prevalence of arthropathy with 7.1% having rheumatoid arthritis (RA). In a prospective study 168 reservation residents (74%) were evaluated. Complete HLA typing identified 57 haplotypes, many of which probably arose via HLA-A/B or B/D recombination. The number of founder haplotypes appeared to be about 20. The population frequency of DR4 (including DRw9, formerly designated 4 X 7) was 67%; for RA it was 100% (p less than 0.05). Apparent DR4 homozygotes, a number of the RA patients, and family members were selected for further study in a mixed lymphocyte culture (MLC) test and with 8th International Workshop cellular and serologic reagents. In MLC with homozygous typing cells (HTC), non of the DR4+ cells typed for any known HLA-D specificity, although they reacted to all DR4 antisera on the local panel. However, 8th International Workshop DR antisera revealed patterns of reactivity with non-DRf4 reagents consistent with the MLC. A minimum of three DR4 variants, one DRw9 variant, and a specificity related to both DR4 and DR2 are required to explain both the cellular and serologic reactions. For the present, we are designating the antigens as DR4.1chip, DR4.2chip, DR4.3chip, DR9chip, and DR(2 X 4)chip. No single variant of DR4 was characteristic of the RA patients in this Amer-indian population.