Intranasal infection of ferrets with a virulent Clone (7a) of the recombinant influenza virus A/PR/8/34—A/England/939/69 (H3N2) produced a fever approximately 24 h in duration beginning about 29 h after infection. The origin of this fever has been investigated as an indication of what might happen in influenza in man. The systemic production of fever by virus interaction with phagocytes in the reticuloendothelial system appeared unlikely because insufficient virus escaped into the bloodstream. Ten half-hourly i.v. injections of 108 50%0 Egg-Bit Infectious Doses (EBID50) of virus were needed to produce a fever of short duration (3-8 h). Yet, after the intranasal infection, which results in the 24 h fever, the total virus content in the nasal mucosa was less than 108 EBID50 before the onset of fever and only reached 108.5 EBID50 for 4 h during fever. Also, just before or during the fever produced by intranasal infection, influenza virus antigens could not be detected by fluorescent antibody in the spleens of the animals but were detected in animals receiving a single bloodstream injection of 108 EBID50 of virus. Fever is more likely to result from release of leucocyte pyrogen by virus-phagocyte interaction in the upper respiratory tract. A pyrogen active in ferrets with the characteristics of leucocyte (endogenous) pyrogen was produced by incubating influenza virus with ferret peripheral phagocytes in vitro. A pyrogen with similar properties was released by incubation of nasal inflammatory cells collected from infected febrile ferrets and many of the cells were shown by fluorescent antibody to have interacted with influenza virus.