Eighty-eight bone marrow transplant recipients were studied for development of cytomegalovirus (CMV) infections and associated cytotoxic lymphocyte responses. Sixty-one patients developed CMV infection that was diagnosed by virus isolation (18 patients), fourfold rises in serum antibodies (13), or both (30). Interstitial pneumonitis developed in 27 patients. Among patients tested during infection, HLA-restricted, CMV-specific cytotoxic T cell responses occurred in 25 patients, and non-restricted, non-T cell cytotoxic responses, or responses of undetermined cell type, occurred in 10 patients. Levels of CMV-specific cytotoxicity in infected and uninfected patients were compared in two ways. Eighty-nine percent of patients (32 of 36) with cytotoxicity greater than or equal to 15% lysis (50:1 effector-to-target-cell ratio) and 100% of patients (21 of 21) with sequential increases in cytotoxicity of greater than or equal to 15% lysis were infected. The median time of occurrence of CMV-specific cytotoxic responses preceded the median onset of viral shedding by 1.4 weeks, or rises in titers of serum antibody by 1.7 weeks, and of interstitial pneumonitis by 2.5 weeks. Immune competence, as demonstrated by survival from infection, was always associated with a CMV-specific cytotoxic response. The HLA-restricted cytotoxic T cell response appears to be important as an early host-defense mechanism and an early diagnostic evidence of infection.