The murine γ-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8 + T cells (CD62L lo) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2 b) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8 + T cells in the blood expressing a Vβ4 + phenotype. Interestingly, the Vβ4 dominance was also seen, to varying extents, in H-2 k, H-2 d, H-2 u, and H-2 q strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vβ4 bias of the T cells, the Vβ4 +CD8 + expansion was absent in H-2IA b–deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody–depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4 + T cells and by a viral superantigen presented by MHC class II glycoproteins to Vβ4 +CD8 + T cells.