Single H2K^b, H2D^b and double H2K^bD^b homozygous knockout (KO) mice were generated and their peripheral CD8⁺ T cell repertoires compared to that of C57BL/6 (B6) mice. Limited (10 – 20 %, H2D^b), substantial (30 – 50 %, H2K^b) and profound (90 %, H2K^bD^b) reduction of peripheral CD8⁺ T cells was observed in KO mice, without Vβ diversity alteration. Classical class Ia molecules therefore ensure most but not all of the peripheral CD8⁺ T cell repertoire education. As expected, H2K^b but also H2D^b KO mice developed choriomeningitis following intracranial infection by lymphocytic choriomeningitis virus with the same kinetics, lethality and CD8⁺ cell implication as wild‐type B6 mice. By contrast, H2K^bD^b (class Ia^–Ib⁺) KO mice survived. Choriomeningitis of H2D^b KO mice was linked to the development of a subdominant (in normal B6 mice) H2K^b‐restricted cytotoxic T lymphocyte response. Mice expressing a restricted set of histocompatibility class I molecules should represent useful tools to evaluate the immunological potentials of individual MHC class I molecules.