We studied the effect of the addition of omeprazole (20 mg once a day) to treatment with pancreatin (Pancrease, Cilag, Herentals, Belgium), two or four capsules three times a day, on fecal fat excretion in a double-blind, crossover fashion in nine patients with cystic fibrosis having persistent steatorrhea while taking Pancrease, two capsules three times a day (mean fecal fat excretion, 22.3%; range, 12% to 44%). Neither doubling of the dose of Pancrease nor addition of omeprazole to the lower dose of Pancrease significantly reduced fecal fat excretion (mean, 19.6% [range, 10% to 34%]; mean, 16.4% [range, 6% to 32%], respectively). However, addition of omeprazole to the higher dose of Pancrease (four capsules three times a day) significantly reduced fecal fat excretion when compared with the two doses of Pancrease alone (mean, 10.7%; range, 4% to 25%; P less than 0.01). We conclude that adjunct therapy with omeprazole reduces fecal fat excretion in cystic fibrosis provided that a high dose of Pancrease is supplied.