Persistent infections with viruses such as HIV, Epstein–Barr virus, cytomelagovirus, and hepatitis B and C viruses continue to be major human health problems. Immunocytotherapy for persistent viral infections has proven successful in animal models but less effective in humans. While the requirement of antigen-specific CD8⁺ T cells is known, the precise role of CD4⁺ T cells as regards specific priming, numbers needed, and interaction with CD8⁺ T cells is less clear. To address these issues, we used a mouse model of persistent virus infection in which adoptive transfer of T cells effectively purges virus from all tissues. We demonstrate that (1) inclusion of antigen-specific CD4⁺ in addition to CD8⁺ T cells is mandatory for efficient and long-term virus control. Neither naive nor CD4⁺ T cells with specificity for a different virus are sufficient. (2) The minimal numbers of virus-specific T cells required for virus clearance from sera and tissues are 350,000 virus-specific CD8⁺ and 7000 virus-specific CD4⁺ T cells or approximately 5 × 10⁷ CD8⁺ and as few as 1 × 10⁶ CD4⁺ T cells per square meter of body surface area, a CD8:CD4 ratio of 50:1. (3) Production of interferon-γ, obligatory for resolution of persistent infection, is dependent on the interaction of virus-specific CD4⁺ and CD8⁺ T cells. (4) Maintenance of CD8⁺ T cell effector functions after adoptive transfer is directly proportional to the amount of cotransferred, virus-specific CD4⁺ T cells.