In Caucasian populations, rheumatoid arthritis (RA) is generally associated with serologic HLA-DR4 specificity. In order to refine this correlation in the HLA-D region, we used six different probes pertaining to this locus: DRβ, DQβ, DQα, DOβ, DPβ and DPα. In this step, pooled RA and control DNA were hybridized with DRβ and DQβ probes after digestion with 12 different endonucleases. Some bands appeared specific in the RA pool. In fact, with genomic DNA from 13 unrelated typed RA patients and 12 matched or partially matched control cells, these bands were revealed to be related to DR4 and/or DR1, with DRβ and DQβ probes hybridizing BamHI, EcoRV, PvuII and StuI digests. With other probes, no differences could be related to RA disease. The polymorphism detected by these probes was suggestive of a gradient of decreasing complexity from DRβ to DOβ through DQβ and DPβ, which could reflect discrete functions of each subregion.