In the majority of patients, pancreatin microsphere preparations containing 25,000–40,000 FIP units of lipase will lead to a clinical improvement and reduction of steatorrhea in patients with exocrine pancreatic insufficiency. In patients failing to respond, the following stepwise procedure is recommended: increasing enzyme dosage; checking the patient’s compliance; reevaluating the diagnosis; and as a last resort to decrease fat intake or adding H<sub>2</sub>-blockers or proton pump inhibitors. Although this stepwise procedure is time-consuming, it is necessary to prevent in patients not responding to pancreatic enzyme substitution the development of late complications of exocrine pancreatic insufficiency.