The effect of the non-specific immunomodulator polyinosinic-polycytidylic acid (pl:C) on the resistance to experimental salmonellosis was studied in the mouse. The polynucleotide was unexpectedly found to decrease the innate relative resistance of the mouse to this intracellular infection. pl:C (100 micrograms/mouse) injected 24 h before either intravenous (i.v.) or intraperitoneal (i.p.) challenge resulted in an increased intracellular rate of growth of the Salmonella in the liver, but did not affect the initial extracellular survival of the bacteria in the peritoneal cavity. By contrast, pl:C did not affect the course of mouse peritonitis caused by E. coli O18:K1, which multiplies extracellularly or that of Listeria monocytogenes, which, like Salmonella, grows intracellularly in the liver. The effect of pl:C on salmonellosis could not be explained by production of alpha or beta interferon (IFN) since it could not be demonstrated by injecting purified IFN nor could it be abolished by injecting neutralizing anti-IFN antibodies. Thus, pl:C seems to have a specific effect on salmonellosis by impairing the growth restriction of these bacteria in the liver macrophages.