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