Formation of interferon-γ (IFN-γ) and tumor necrosis factor (TNF) during Salmonella typhimurium infection was investigated in lipopolysaccharide (LPS)-sensitive C3H/HeN and C57BL/10ScSn(B10ScSn), and LPS-resistant (Ipsdmutant) C3H/HeJ and C57BL/10ScCr(B10ScCr) mice. When infected with 50 colony-forming units (CFU) of S. typhimurium C5, C3H/HeN and BlOScSn mice became hypersensitive to the lethal effect of LPS. In the case of Ipsdmutants, only C3H/HeJ mice became hypersensitive to LPS, while BlOScCr mice remained resistant. C3H/HeJ as well as BlOScSn mice produced significant amounts of plasma IFN-γ on day 3 after infection. By this time bacterial CFU in the liver of B10ScSn and C3H/HeJ mice were 106.7 and 107.1, respectively. In B10ScCr mice, however, IFN-γ was not detectable although bacteria present in the liver exceeded 108 CFU. On the other hand, plasma TNF was not detectable in any of the mouse strains during S. typhimurium infection. When S. typhimurium-infected mice were challenged with LPS on day 3, significant amounts of plasma TNF were measured in C3H/HeN and B10ScSn mice, while in the Ipsdmutant C3H/HeJ and B10ScCr mice plasma TNF was undetectable.