The correlates of protective immunity to disease-inducing viruses in humans remain to be elucidated. We determined the kinetics and characteristics of cytomegalovirus (CMV)–specific CD4⁺ and CD8⁺ T cells in the course of primary CMV infection in asymptomatic and symptomatic recipients of renal transplants. Specific CD8⁺ cytotoxic T lymphocyte (CTL) and antibody responses developed regardless of clinical signs. CD45RA⁻CD27⁺CCR7⁻ CTLs, although classified as immature effector cells in HIV infection, were the predominant CD8 effector population in the acute phase of protective immune reactions to CMV and were functionally competent. Whereas in asymptomatic individuals the CMV-specific CD4⁺ T-cell response preceded CMV-specific CD8⁺T-cell responses, in symptomatic individuals the CMV-specific effector-memory CD4⁺ T-cell response was delayed and only detectable after antiviral therapy. The appearance of disease symptoms in these patients suggests that functional CD8⁺ T-cell and antibody responses are insufficient to control viral replication and that formation of effector-memory CD4⁺ T cells is necessary for recovery of infection.