Splenic lymphocytes from C3H/HeN mice were primed in vivo or in vitro with the interferon inducer poly inosine:cytosine (Poly I:C) or in vitro with interferon α (IFNα) and evaluated for their natural killer (NK) activity after exposure to hyperthermia for defined periods. Lytic activity against cells of the NK-susceptible Moloney lymphoma cell line YAC by Poly I:C- or IFNα-primed spleen cells exhibited thermotolerance to 41, 42 and 43°C exposure compared to unprimed cells. Spleen cells were also incubated for 1 h at 40 or 37°C prior to exposure to 42°C. Incubation at 40°C produced a modest increase in thermal resistance to 42°C by otherwise unprimed spleen cells. Spleen cells that had been primed by Poly I:C or IFNα followed by 1 h at 40°C were rendered even more resistant to hyperthermia at 42°C. These data suggest that two host responses to viral infection, fever and production of IFNα, may endow cells involved in the inflammatory response (in this case NK cells) with resistance to more severe stress. Further, IFNα and fever may synergize in this protective mechanism.