It has been previously demonstrated that the exposure of the lower esophageal mucosa to acid and pepsin results in significant increase in salivary protective factors secretion, mediated by the esophago-salivary reflex. The impact of the upper esophageal mucosal exposure to acid and pepsin on salivary secretory response remains unknown. To investigate the rate of salivary protective factors secretion during the upper esophageal mucosal exposure to acid and pepsin and to compare with the corresponding results recorded during the lower esophageal mucosal exposure, in the same group of asymptomatic volunteers. The study was conducted in 10 asymptomatic volunteers. Salivary samples were collected during the esophageal mucosal exposure to saline, followed by acid/pepsin and the final saline, using the esophageal perfusion catheter. Salivary bicarbonate and non-bicarbonate buffers were analyzed using TitraLab. Salivary mucin and protein were quantified through PAS and Lowry methodologies, respectively, whereas PE2 using radioimmunoassay. Statistical analysis was performed using Σ-Stat software. The rate of salivary bicarbonate secretion was significantly higher (3.1-fold) during the upper versus the lower esophageal mucosal exposure to acid and pepsin (87.5 ± 14.4 vs. 28.0 ± 7.70 μEq/min, p < 0.05). The volumes of saliva, pH, salivary protein, mucin and PE2 were similar in both esophageal perfusions. Threefold stronger secretion of salivary bicarbonate could be a major factor protecting the upper esophageal mucosa. This phenomenon may represent an ultimate defense mechanism potentially preventing further complications within the upper esophageal mucosa; however, it needs to be confirmed in patients of gastroesophageal reflux disease.