Forty-five patients were prospectively studied during the first 100 days after allogeneic marrow transplant to determine the relationship between cytomegalovirus-specific gamma-interferon and interleukin 2 production by peripheral blood mononuclear cells and CMV infection. IL-2 production was significantly lower than normal throughout the study period (P = 0.0001). In contrast, mitogen-induced gamma-interferon production was in the normal range by days 41-60 while CMV antigen induced gamma-interferon production by PBMC was normal by 81-100 days after transplant. Antibody- and complement-depletion studies showed that T4 helper cells were capable of gamma-interferon production in response to CMV antigen despite deficient IL-2 production. Neither gamma-interferon nor IL-2 production distinguished CMV-infected from uninfected patients. However, CMV-infected patients had significantly more T8 cytotoxic/suppressor cells than did uninfected patients by 81-100 days after transplant (P = 0.001). In vitro addition of IL-2 significantly increased gamma-interferon production by PBMC from patients with reduced production, suggesting that decreased gamma-interferon production may be related to deficient IL-2 production. Deficiencies in both CMV-specific IL-2 and gamma-interferon production may contribute to the high frequency and severity of CMV infection after marrow transplantation.