Percent survival was measured in male rats injected intravenously with live Salmonella typhimurium when plasma and tissue zinc levels were manipulated. Alzet pumps implanted intraperitoneally infused zinc gluconate or sodium gluconate (controls) from the onset of infection to 72 h postinfection. Plasma and tissue zinc levels were manipulated by infusing (i) 180 micrograms of Zn per h to achieve supranormal plasma and tissue zinc concentrations, (ii) 120 micrograms of Zn per h to prevent the infection-induced fall and to maintain plasma zinc levels at noninfection levels while raising tissue levels above that of infected controls, and (iii) 30 micrograms of Zn per h to increase tissue zinc levels while allowing the infection-induced decrease in plasma zinc. Preventing the fall in plasma zinc while raising liver zinc to supranormal levels enhanced rather than reduced percent survival; raising plasma and liver zinc to supranormal levels returned survival to control levels. Loading the liver with an excess of zinc without changing plasma zinc (30 micrograms of Zn per h) did not increase percent survival in the infected host. Pretreatment or administration of zinc at the time of infection led to increased percent survival compared with administration of zinc 4 h after the onset of infection.