The ability of DT-5461, a chemically synthetic low-toxic lipid A analogue, to activate anti-Salmonella activity in C3H/HeN mice was examined. Previous intraperitoneal (i.p.) injection of DT-5461 (100 micrograms or more/mouse) significantly hindered the bacterial growth in the peritoneal cavities of the mice after the i.p. infection with Salmonella typhimurium LT2 strain. The effect was the maximum when DT-5461 was given 6 h before the challenge. The injection of DT-5461 6 h in advance could also confer protection against the infection. Bactericidal activity enhancement was also seen in mice that had been injected with a small amount of recombinant murine IFN-gamma (10(3) U per mouse) and non-effective dose (10 micrograms) of DT-5461 together 6 h before the challenge. Bactericidal effect enhancement was seen in mice that had been injected with IFN-gamma at 6 h and DT-5461 at 3 h before the challenge, while it could be hardly seen in mice injected with them in a reversed order. The i.p. injection of DT-5461 recruits the exudate cells into the peritoneal cavities, and the phagocytic and bactericidal abilities of the macrophages in the exudate cells are apparently elevated. The mechanisms of non-specific resistance enhancement induced by DT-5461 were discussed.