The effect of the addition of sodium bicarbonate, aluminum hydroxide, magnesium hydroxide, calcium carbonate, or cimetidine to supplemental pancreatic enzyme therapy was investigated in patients with severe exocrine pancreatic insufficiency. Steatorrhea was reduced with the administration of three enzyme tablets with meals (73 vs 29 g/24 hr). The coadministration of enzyme tablets with either sodium bicarbonate (16.6 g/24 hr, P = 0.08), or aluminum hydroxide (18.4 g/24 hr, P = 0.029) yielded a greater reduction in steatorrhea than enzymes alone (29 g/24 hr). Neither magnesium-aluminum hydroxide (36.3 g/24 hr, P = 0.22), nor calcium carbonate (39.0 g/24 hr, P = 0.029), improved efficacy of enzyme therapy and, in fact, tended to enhance steatorrhea. With the administration of cimetidine there was no significant effect on steatorrhea compared to enzymes alone (32.1 vs 29 g/24 hr, P greater than 0.3). Intraduodenal lipase activity following test meals was found to be a poor predictor of the effectiveness of antacid therapy in improving the efficacy of supplemental enzymes.