Early clearance of a thymidine kinase-deficient strain of herpes simplex virus type 2 from the female genital tract required T-cell-produced gamma interferon (IFN-gamma). Transfer of activated CD8+ T cells to irradiated C57BL/6 mice resulted in rapid virus clearance, but clearance was greatly delayed in recipients deficient in the IFN-gamma receptor (IFN-gammaR). Early virus clearance was demonstrated in radiation chimeras in which IFN-gammaR expression was limited to parenchymal cells, but resolution was significantly delayed in chimeras deficient in IFN-gammaR expression and chimeras expressing IFN-gammaR only on hematopoietic cells. Together, these results suggest that early IFN-gamma-mediated protection was manifested mainly by stimulation of genital parenchymal cells.