The involvement of human leukocyte antigen determinants for the response of mumps virus-specific cytotoxic T lymphocytes in humans was studied. The cytotoxic T lymphocytes could only lyse virus-infected allogeneic cells with which they shared a particular human leukocyte antigen, e.g., Bw52 or B7. The existence of Bw52 in the subjects who received a booster immunization with live mumps vaccine was associated with a significantly higher cytotoxic T-lymphocyte response than that of subjects without the gene. Although a donor-dependent difference in the recognition of human leukocyte antigen-A2 suggests the complexity of the genetic mechanisms involved, the results are largely consistent with the concept of major histocompatibility complex-linked genetic control of virus-specific cytotoxic T-lymphocyte response.