We have studied the complexity of HLA class II region in DR7 bearing extended haplotypes by restriction fragment length polymorphism (RFLP). Genomic DNA from homozygous cell lines and from unrelated individuals was digested with a number of restriction endonucleases and probed with DR alpha, DR beta, DQ alpha and DQ beta cDNA probes. We detected RFLPs that distinguished subspecificities of DRA, DRB1, DQA1 and DQB1 chain genes. On the basis of polymorphism in these genes, three distinct types of DR7 bearing extended haplotypes could be identified: (1) B44 or Bw47 or B14, DR7a (DRA1, B1.1), DRw53a (DRA1,B4), DQw2 (DQA1.1, B1.1); (2) B13 or B40, DR7b (DRA1, B1.2), DRw53a (DRA1, B4), DQw2 (DQA1.1, B1.1); and (3) Bw57, DR7c (DRA2, B1.2), DRw53b (DRA2, B4), DQw9 (DQA1.2, B1.2). Available evidence indicates that independent examples belonging to a haplotype were similar in RFLP patterns, suggesting that most examples of an extended haplotype belonging to a subtype are similar. The results in the present study have important implications for immune function and disease susceptibility.