We have studied HLA-A, B, C, and DR antigens in 37 unrelated Caucasian families with multiple cases of definite or classic rheumatoid arthritis (RA). HLA-DR4 was observed in 26 of 36 probands tested (73 per cent); and six of the 10 DR4 negative probands possessed DR1. HLA haplotype sharing among affected siblings was more often observed than would be expected if RA and HLA haplotype were segregating independently (p = 0.041). In families with a DR4-heterozygous parent, the affected parent's HLA haplotype co-segregates significantly with RA among the offspring (p less than 0.005); and in families where both parents are unaffected, occurrence of RA among the offspring co-segregates significantly with DR4 haplotype (p = 0.004). Our data strongly indicate that at least one genetic determinant for susceptibility to RA resides in the HLA region, closely linked to the DR locus, or that the susceptibility determinant may be an epitope or structure that is commonly found on DR4 molecules but occasionally on other DR molecules.