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The goal of our study was to characterize the apoptotic response of herpes simplex virus (HSV)-infected, human epithelial HEp-2 cells to extrinsic treatments through the Fas receptor. Initially, we defined the Fas response of these cells. We found the following: (1) Treatment of HEp-2 cells with anti-Fas antibody or Fas ligand (FasL) alone did not induce apoptosis. (2) In addition, these inducers did not activate NF-κB in these cells. (3) The addition of cycloheximide (CHX) during these treatments caused a dramatic increase in programmed cell death. (4) HEp-2 cells infected with HSV for 6 h prior to anti-Fas plus CHX treatment were nonapoptotic, and (5) these cells possessed nuclear NFκB. (6) HSV blocked anti-Fas or FasL plus CHX-induced apoptosis in HEp-2 cells that stably expressed a dominant-negative form of IκBα. These results indicate that HSV infection can block the process of Fas-mediated apoptosis through a mechanism that is independent of viral activation of NFκB. Our findings help define the molecular mechanisms involved in HSV evasion of the cytokine-driven, innate immune response in human epithelial cells.