Infection of mice with a series of heterologous viruses causes a reduction of memory CD8+ T cells specific to viruses from earlier infections, but the fate of the virus-specific memory CD4+ T cell pool following multiple virus infections has been unknown. We have previously reported that the virus-specific CD4+ Th precursor (Thp) frequency remains stable into long-term immunity following lymphocytic choriomeningitis virus (LCMV) infection. In this study, we questioned whether heterologous virus infections or injection with soluble protein CD4 Ags would impact this stable LCMV-specific CD4+ Thp memory pool. Limiting dilution analyses for IL-2-producing cells and intracellular cytokine staining for IFN-γ revealed that the LCMV-specific CD4+ Thp frequency remains relatively stable following multiple heterologous virus infections or protein Ag immunizations, even under conditions that dramatically reduce the LCMV-specific CD8+ CTL precursor frequency. These data indicate that the CD4+ and CD8+ memory T cell pools are regulated independently and that the loss in CD8+ T cell memory following heterologous virus infections is not a consequence of a parallel loss in the memory CD4+ T cell population.