Luminal release of esophageal epidermal growth factor (EGF) into the perfusing solutions (saline, HCl, and HCl/pepsin), aspirated with the newly developed esophageal perfusion catheter, was measured in 20 healthy volunteers (12 male, 8 female; mean age 40 yr; range 30-56 yr). A potential salivary contamination was excluded by a complete seal (with two balloons) of perfused esophageal segment and by a simultaneous, carefully monitored, collection of saliva. The concentration of EGF in each of 16 fully recovered 2-min perfusion samples was measured by RIA kit (Amersham, IL). The concentration of EGF in recovered NaCl perfusate varied between (mean +/- SEM) 1.78 +/- 0.19 and 2.14 +/- 0.14 ng/ml, whereas output varied between 9.25 +/- 0.98 and 11.14 +/- 0.82 ng/min. During perfusion with HCl, both the concentration of EGF within the esophageal perfusate and its secretion declined significantly to a value of 0.68 +/- 0.17 ng/ml (p < 0.0001) and 3.56 +/- 0.90 ng/min (p < 0.0001), respectively. Introduction of pepsin into an acidic perfusion solution (0.5 mg/ml of HCl) resulted in a significant increase in EGF concentration (1.99 +/- 0.36 ng/ml; p < 0.001) and output (10.24 +/- 1.84; p < 0.01), compared with EGF values recorded during perfusion with HCl. EGF output, calculated from a sealed 7.5-cm segment of the esophagus, was 10.39 +/- 0.89 ng/min, and was maintained at a steady state throughout an entire saline perfusion procedure. We present evidence that human esophageal mucosa has an enormous EGF secretory potential. The rapid esophageal EGF secretory response to intraluminal challenge with aggressive factors implies its role in the maintenance of the mucosal integrity.