We previously studied the lung Vβ TCR repertoire of C57BL/6 mice during primary infection with the pathogen Histoplasma capsulatum. We observed a consistent oligoclonal expansion of Vβ4+ T cells during the peak of infection and early stages of resolution. The Vβ4+ family played a role in protective immunity against the fungus. Depletion of this subpopulation of T cells hindered optimal clearance of infection from tissues. In this report we analyze the flux of the Vβ TCR repertoire in the lungs of C57BL/6 mice with reinfection histoplasmosis. We observed a significant increase in Vβ6+ T cells on days 7, 10, and 14, the peak and early resolution phases of infection. This skewing was preceded by an increased number of memory T cells within Vβ6+ cells. The VDJ sequences of Vβ6 chains were oligoclonal during the early stages of the infection, suggesting that the expansion was driven by a small number of Ags. More than 96% of the expanded Vβ6+ cells were CD4+. Depletion of Vβ6+ T cells but not Vβ4+ T cells induced a modest but significant delay in fungal clearance. Simultaneous depletion of Vβ4+ and Vβ6+ T cells induced a more pronounced impairment of host resistance. These studies illustrate the dynamic interactions between Vβ families in the response to microbial challenge.