A comparison of the major histocompatibility complex (Mhc) region between human and mouse highlights both stability and differences. The class II and class III regions are orthologous; they probably existed in the ancestor in a similar organization and were not subjected to major rearrangement. The class I genes, by contrast, are definitely paralogous, having been reorganized several times. As long as only class I genes were identified, the class I regions of human and mouse were difficult to compare directly. The identification of non-class I genes has allowed a comparative map to be drawn, which shows that the class I region is orthologous between human and mouse as well. The lack of orthology specifically applies to the class I sequences. However, the comparative map shows that the non-orthologous class I sequences occupy homologous locations with regard to the conserved genes. I propose a model to explain this paradox. The conserved genes may represent samples of a dense "framework" of genes whose alterations are deleterious. The homologous positions occupied by class I genes would thus represent the few permissive places allowing major perturbations. The evolution of the class I sequences, by duplication and deletion, independently in the two species, has taken place within the scope defined by the framework: insertion at the permissive places, and expansion by creation of class I-related DNA by duplication, thus pushing back the boundaries of the framework.