Murine gammaherpesvirus 68 ([gamma]HV68, MHV-68)-specific CD4 T cells control [gamma]HV68 infection by reducing the frequency of latently infected cells and by inhibiting viral replication. We have previously demonstrated that CD4 T cells do not require CD8 T or B cells to control [gamma]HV68 replication, demonstrating a helper-independent activity of CD4 T cells during [gamma]HV68 infection. The effector mechanism(s) required for this helper-independent function of CD4 T cells and for the inhibition of the establishment of latency by CD4 T cells are not known. Since IFN[gamma] has been previously shown to be important for control of acute, latent, and persistent [gamma]HV68 infection, we tested the hypothesis that CD4 T cells require IFN[gamma] to limit [gamma]HV68 latency and replication. We utilized a previously described system in which T cell receptor (TCR) transgenic T cells (DO.11.10) and a recombinant virus ([gamma]HV68.OVA) allow for evaluation of high numbers of virus-specific CD4 T cells during both acute and latent infection. We show here that virus-specific CD4 T cells require IFN[gamma] for their anti-viral function in both acute and latent [gamma]HV68 infection. We additionally show that an in vitro derived T helper type 1 (TH1) CD4 T cell clone, which produces IFN[gamma], inhibits [gamma]HV68 replication after adoptive transfer into RAG mice. Together, data presented here demonstrate that both CD4 T cell-mediated helper-independent control of [gamma]HV68 replication and inhibition of the establishment of [gamma]HV68 latency require IFN[gamma].