The coexistence of nontropical sprue and advanced pancreatic insufficiency is uncommon. The purposes of this report are to: (a) describe 3 patients with non-tropical spruc and severe pancreatic insufficiency, (b) determine the frequency, magnitude, and clinical importance of diminished pancreatic secretion in nontropical sprue, and (c) assess whether patients with pancreatic insufficency secondary to chronic pancreatitis or pancreatic cancer have jejunal mucosal histologic abnormalities. In each of 3 patients with nontropical sprue and associated severe exocrine pancreatic insufficiency, an optimal clinical response required the appropriate treatment of both causes of malabsorption. Of 31 subjects with proved nontropical sprue, cholecystokinin-stimulated duodenal tryptic activity or lipolytic activity (or both) was reduced in 13 (42%) but severely reduced in only the three case reports (10%). The morphologic structure of the small bowel was normal in 21 patients with primary pancreatic insufficiency secondary to chronic pancreatitis or pancreatic cancer. Mild-to-moderate exocrine pancreatic insufficiency is a frequent finding in untreated nontropical sprue, is presumably reversible, and rarely contributes to the development of steatorrhea. However, if patients with nontropical sprue fail to respond to a gluten-free diet, coexistent severe pancreatic insufficiency is a possible cause for treatment failure.