HLA‐B*0702 transgenic mice (expressing a chimeric heavy chain with a murine α3 domain: HLA‐B7^mα3) in which the H‐2K^b and H‐2D^bclass I‐a (Cl I‐a^–/–) genes have been inactivated were compared with H‐2K^bD^bCl I‐a^+/+ positive controls. Expression of the HLA‐B7^mα3 molecules resulted in a 3‐ to 4‐fold increase in peripheral CD8⁺ T lymphocyte numbers compared to H‐2 Cl I‐a^–/– knockout mice. These cells show a diversified TCR repertoire. Following influenza infection, a significant improvement in HLA‐B0702‐restricted cytotoxic T lymphocyte (CTL) responses was observed in HLA‐B7^mα3, H‐2 Cl I‐a^–/– compared to HLA‐B7^mα3, H‐2 Cl I‐a^+/+ mice. The CTL response of infected HLA‐B7^mα3, H‐2 Cl I‐a^–/– mice was directed against the nucleoprotein (NP) 418–426 epitope in which mutations have accumulated. Whereas all NP 418–426 variant peptides induced a CTL response, cross‐reactivity to the variants was affected. These NP mutations could have been selected over time in humans for the virus to escape HLA‐B0702‐restricted CTL responses since a similar response was seen in humans with, as in mice, altered cross‐recognition of the NP 418–426 variants. These animals may prove a suitable model to study HLA‐B0702‐restricted CTL responses.