The availability of mutant and gene targeted knockout mice with defects in components of cellular cytotoxicity mediated by either the Fas or the exocytosis pathway permitted an analysis of their role in recovery from poxvirus infections. Ectromelia (EV), a natural mouse pathogen causing mousepox, the closely related orthopoxviruses cow pox (CPV) and vaccinia virus (VV), each encode serpins that inhibit Fas mediated apoptosis and lysis of target cells. Nevertheless, distinct differences were seen when the three viruses were inoculated into perforin-;deficient mice: highly resistant C57Bl/6 mice became susceptible to low doses of EV; resistance to CPV increased whereas there was no effect on VV infections. Absence of the cytolytic granule associated granzymes (gzm) A and B rendered C57Bl/6 mice increasingly more susceptible to EV infections. Lack of both gzms rendered them as susceptible as perforin deficient mice, despite the presence of functionally active perforin. Elevated EV titres in liver and spleen of gzmA×B deficient mice, early after infection and before cytotoxic T cells were detectable, strongly suggests that these two gzms exert an antiviral effect by a mechanism distinct from effector molecules of NK and cytotoxic T cells. Copyright © 2003 John Wiley & Sons, Ltd.