Bam HI DR-beta and DQ-beta restriction fragment length polymorphisms (RFLPs) were found with increased frequency in white persons with seropositive rheumatoid arthritis as compared with control subjects. DR-beta 4.8-, 5.2-, and 7.0-kilobase (kb) RFLPs were observed in 86.5 percent of rheumatoid arthritis patients and in 56 percent of control subjects (p = 0.001, relative risk [RR] = 5.0). The 6.0-kb RFLP was present in 79 percent of rheumatoid arthritis patients and 32 percent of control subjects (p = 0.0002, RR = 8.0). The 4.8-, 5.2-, and 7.0-kb RFLPs correlated with DR4, -7, -9, and -w53 phenotypes and the 6.0-kb RFLP correlated only with DR4. Thus, these RFLPs do not appear to be disease-specific. A DQ-beta 3.2-kb RFLP was found in 63.5 percent of rheumatoid arthritis patients and in 38.0 percent of control subjects (p = 0.01, RR = 2.8). This fragment was frequently found in persons expressing DR1 and DQw1 phenotypes. Probes consisting of the first exon of the DR-beta-I and DR-beta-IV genes, respectively, only hybridized with the 5.2- and 6.0-kb RFLPs. These data suggest that more than one gene within the major histocompatibility complex contributes to susceptibility to seropositive rheumatoid arthritis in white persons.