In patients with pancreatic exocrine insufficiency, the use of pancreatic enzyme does not abolish steatorrhea in some cases. We carried out a long-term prospective study in an attempt to clarify the effectiveness of the associated use of famotidine to enzymatic supplementation on fat absorption and nutritional parameters of patients with pancreatic insufficiency due to cystic fibrosis. We studied 10 patients, mean age 12.5 years, with persistent steatorrhea on enzymatic supplementation. A double-blind crossover design was used and famotidine (1 mg/kg/day) or placebo was given as adjuvant to enzymatic preparations for either of two six-month periods. A statistically significative reduction in fecal wet weight (P less than 0.0001), an improvement in the coefficient of fat absorption (P less than 0.01) and in the steatocrit values (P less than 0.028) were found on famotidine. Moreover, the weight and the height increases were greater after famotidine than after placebo period (respectively, P less than 0.012 and P less than 0.01); also the serum calcium and triglycerides levels were higher after the period on famotidine (respectively, P less than 0.0025 and P less than 0.025). No adverse effects of famotidine were noted. These data suggest that famotidine is a useful adjuvant to pancreatic enzyme therapy in patients with severe pancreatic insufficiency and persistent maldigestion on large doses of pancreatic supplements; in fact, famotidine improves not only fat absorption but the nutritional status of the patients.