In a double-blind, randomized crossover study, the hypotheses were tested that more powerful inhibition of gastric acid secretion by adjuvant omeprazole further improves the efficacy of pancreatic enzyme replacement therapy compared to adjuvant cimetidine and that excluding the influence of pH-related factors, by virtually complete inhibition of gastric acid secretion with 60 mg omeprazole daily, does not lead to total elimination of steatorrhea. During both adjuvant cimetidine and omeprazole treatment, fecal fat excretion was significantly lower compared to pancreatin monotherapy (P < 0.01). Omeprazole showed a trend towards a more favorable decrease of fecal fat excretion compared to cimetidine but no statistically significant difference. Steatorrhea was almost never abolished, even during 60 mg omeprazole daily. Generally, pH-related factors are considered to explain an inadequate therapeutic response during pancreatic enzyme replacement therapy. However, this study indicates that in vivo other factors also play a significant role.