The HLA-D region of the major histocompatibility complex (MHC) is characterized by a remarkable diversity. Most of the HLA class II genes are highly polymorphic, and in addition, the number and organization of individual loci in that region varies in different haplotypes. This extensive allelic polymorphism of immune response genes has well-known functional implications. Within the HLA-D region, two loci, DQA2 and DQB2 (formerly called DX alpha and DX beta), represent a very special case: the detailed structure of these two genes is entirely compatible with expression, yet their expression has never been demonstrated in any tissue. Consequently, there exists no known corresponding protein product. Pseudogenes are known to accumulate mutations, as observed for instance in the case of HLA-DPA2,-DPB2, or -DRB2 genes. We have therefore investigated the extent of DQ2 genes' polymorphism by DNA sequence comparison and by oligonucleotide hybridization across a large number of different haplotypes, and compared it with other genes in the HLA-D region. We show here that, contrary to the adjacent DQ1 genes, DQ2 genes exhibit little and possibly no polymorphism. This conservation of DQ2 genes in many haplotypes indicates that the DQ1-DQ2 duplication event must have preceeded the extensive diversification of DQ1 genes and raises the puzzling question of why DQ2 genes have remained nonpolymorphic. This suggests that either these genes correspond to an unusually invariant region of the MHC or they are under a strong selective pressure for the conservation of the amino acid sequence of a putative DQ2 gene product. The latter would imply that the HLA-DQ2 genes are expressed into a protein product endowed with essential functional properties.