The present study compares human cytotoxic T-cell responses to two closely related viruses (type A and type B influenza) to understand the antigen-specific elements involved in HLA-linked genetic control of cytotoxic T-cell responses. The HLA antigens function as self antigens that are recognized by cytotoxic T cells sensitized against either virus. However, studies in an informative family indicate that in this family, the HLA antigens preferentially recognized in conjunction with type A influenza (A/HK) differ from the HLA antigens preferentially recognized in conjunction with type B influenza (B/HK). Similarly, population studies demonstrate that some (but not all) donors whose T cells recognized A/HK in conjunction with HLA-A2 failed to recognize B/HK in conjunction with HLA-A2. Thus, HLA-linked regulation must operate by a mechanism(s) that is specific both for the self HLA antigen and the viral antigen. Furthermore, these findings indicate that different HLA antigens may facilitate T-cell responses to different pathogens, which would result in an evolutionary advantage for HLA heterozygosity.