In the present study we demonstrated that a single injection of endotoxin (lipopolysaccharides, E. Coli 0111-B4) into the superior pancreaticoduodenal artery of rabbits induced a dose-dependent acute necrotizing pancreatitis. The lesions observed by light microscopy were significant for 10 μg lipopolysaccharides and were maximal for 20 μg. After 24 h the main findings were edema, acinar cell vacuolisation, polymorphonuclear neutrophil infiltration and tissue necrosis. The pancreatic lesions developed strictly in the area supplied by the artery injected with lipopolysaccharides, without significant intestinal involvement. Since platelet-activating factor (1- O-hexadecyl-2-acetyl- sn-glycero-3-phosphocholine, PAF; 50–500 ng), a phospholipid mediator of endotoxin-induced inflammation and shock, was previously shown to cause an acute necrotizing pancreatitis in rabbits, the role of PAF in the development of acute pancreatitis induced by lipopolysaccharides was studied by evaluating: (1) the synergism between doses of lipopolysaccharides (5–10 μg), which produced a mild tissue injury, and doses of PAF (10 ng) not producing, per se, any significant injury, and (2) the effect of three structurally unrelated PAF receptor antagonists. The results obtained demonstrated that 10 ng of PAF significantly potentiated pancreatic tissue damage induced by 10 μg of lipopolysaccharides. Moreover, PAF receptor blockade resulted in complete prevention of the severe pancreatitis caused by 20 μg lipopolysaccharides with cis(+)-1-[2-hydroxy[tetrahydro-5-[(octadecyl-aminocarbonyl)oxy]methyl]-2-furanyl]methoxy-phosphinyl-oxy]ethyl]-quinolinium hydroxide, SRI 63675 and in a significant reduction of the incidence and the extension of tissue injury with ( RS)-2-methoxy-3-(octadecylcarbamoyloxy)-propyl-2-(3-thiazolio)-ethylphosphate, CV 3988 and 6-(2-chloro-phenyl)-8,9-dihydro-1-methyl-8- (4-morpholinyl-carbonyl)-4 H,7 H-cyclopentyl[4,5]thienol[3,2- f][1,2,4]-triazolo-[4,3-α][1,4]diazepine, WEB 2170. These observations suggest a crucial role of PAF in the pathogenesis of pancreatic tissue damage induced by lipopolysaccharides.