This study investigated whether dietary choline can prevent endotoxin shock. Female Sprague-Dawley rats fed chow or chow plus choline chloride (0.025-0.4%) for 3 days were given lipopolysaccharide (LPS) via the tail vein. Eighty-three percent and 56% of chow-fed rats survived after 2.5 or 5.0 mg/kg LPS, respectively. Choline increased survival in a dose-dependent manner, with maximal effects observed at 0.4%; this dose of choline prevented mortality completely after 2.5 or 5 mg/kg LPS. Choline also improved the microscopic appearance of the lungs and blunted increases in serum aspartate aminotransferase levels. Intracellular Ca²⁺ was monitored in liver and lung macrophages during LPS exposure. Ca²⁺ increases in macrophages from choline-fed rats were blunted by 40-60% compared with chow-fed controls. Feeding choline also blunted tumor necrosis factor- production. Feeding glycine, which prevents macrophage activation via a chloride channel, in addition to choline was even more effective than feeding choline alone, suggesting that glycine and choline act via distinct sites. These data are consistent with the hypothesis that choline diminishes endotoxin shock by preventing macrophage activation.