The functional status of CD4⁺ T cells during establishment of persistent infection with the noncytopathic lymphocytic choriomeningitis virus was assessed and compared to that of cytotoxic CD8⁺ T cells. Functionality of virus-specific CD4⁺ T cells was measured by proliferative responses, cytokine secretion, cognate help, and IFNγ-mediated protection against challenge infection with recombinant vaccinia virus. Functional CD4⁺ T cells were induced early after infection and remained measurable up to 6 weeks but then were rendered unresponsive. In contrast, CD8⁺ T cells were functionally inactivated within 10–15 days. Importantly, functional inactivation of virus-specific CD4⁺ T cells during persistent viral infection seemed to be critical for the survival of the host.