Many believe that intragastric deactivation of lipase accounts for the frequent failure of orally ingested pancreatic enzymes to normalize fat absorption in patients with pancreatic insufficiency. To test this hypothesis, we measured fat absorption from a large test meal in six patients with pancreatic insufficiency after we had instilled Viokase directly into the postcibal duodenum in two doses, one to deliver lipase at about 10% of normal secretory rates and the other at four times this rate. Direct duodenal instillation of neither the low nor the high dose of Viokase, nor the low dose of Viokase plus sodium bicarbonate, normalized fat absorption from the test meal; none of these duodenal instillations significantly improved fat absorption over that after the test meal plus orally ingested Viokase. Despite these various treatments, the patients excreted an average of 25.5 g of dietary fat as opposed to 2.1 g excreted by six normal subjects after the same meal. We conclude that more than just intragastric destruction of lipase underlies the frequent failure of orally ingested pancreatin to normalize fat absorption in pancreatic insufficiency.