The effect of sublethal infection with Salmonella typhimurium on the sensitivity of mice to the lethal activity of lipopolysaccharide (LPS) was studied in C3H/TifF mice. These mice are more resistant to S. typhimurium infection and survive inocula that are lethal for most other strains of mice. Infection of C3H/TifF mice with 2 x 10(4) CFU of S. typhimurium was without lethal effect. However, administration of LPS at different times after infection revealed that the sensitivity of the animals to the lethal activity of LPS increased exponentially, reaching a maximum by 6 to 8 days after infection. Thereafter, it decreased, reaching preinfection values about 4 weeks after inoculation. At the height of sensitivity, the animals were susceptible to less than 1 microgram of LPS compared with 100 or 200 micrograms in noninfected mice. The sensitization to LPS by infection was paralleled by a sensitization to tumor necrosis factor. The time course of development of sensitization to tumor necrosis factor, as well as the time course of its decrease and disappearance, was almost identical to that of LPS.