In many settings hypertriglyceridemia can initiate an episode of acute pancreatitis. Hydrolysis of triglycerides by pancreatic lipase with the local release of large quantities of free fatty acids (FFA) was proposed as the pathogenetic mechanism. An isolated, ex vivo, perfused pancreatic preparation was used. Control preparations remained normal in gross appearance, gained little weight (18 g), extracted O2 and glucose and released CO2, and continued to secrete during a 4 h perfusion period. Serum amylase remained normal (972 CU/100 ml) as did FFA (1.11 meq/l). When triglycerides were added to the perfusate to increase the serum triglycerides to 1600 mg%, the glands became edematous, hemorrhagic and gained considerable weight (52 g) during the 4 h perfusion period. Serum amylase became markedly elevated (2624 CU/100 ml), as did the serum FFA (29.19 meq/l). When FFA were added directly to the perfusate, the glands became edematous, hemorrhagic and gained weight (90 g), but did so much more rapidly than when triglycerides were added. Hypertriglyceridemia can initiate pancreatic injury. The mechanism may be through the release of FFA.