Background: Capsaicin is a specific compound acting on capsaicin-sensitive afferent nerves. Aim: Capsaicin was used to study the different events of human gastrointestinal physiology, pathology, and clinical pharmacology, and possible therapeutic approaches to enhance gastrointestinal mucosal defense in healthy human subjects and in patients with various different gastrointestinal disorders as well as its use with nonsteroidal anti-inflammatory drugs (NSAIDs) in healthy subjects and in patients. Materials and Methods: The observations were carried out in 198 healthy human subjects and in 178 patients with different gastrointestinal (GI) diseases (gastritis, erosions, ulcer, polyps, cancer, inflammatory bowel diseases, colorectal polyps, cancers), and in 69 patients with chronic (Helicobacter pylori positive and negative) gastritis (before and after eradication treatment). The gastric secretory responses and their chemical composition, gastric emptying, sugar loading test, gastric transmucosal potential difference (GTPD) with application of capsaicin alone, after ethanol alone and with capsaicin, indomethacin-induced gastric mucosal microbleeding without and with capsaicin were studied. The immunohistochemical examinations of the capsaicin receptor (TRVP1), calcitonin gene- related peptide (CGRP), and substance P (SP) were carried out in gastrointestinal tract, and especially in patients with chronic gastritis (with and without Helicobacter infection, before and after classical eradication treatment). Classical molecular pharmacological methods were applied to study the drugs inhibiting the gastric basal acid output. Results: Capsaicin decreased the gastric basal output, enhanced the "non-parietal" (buffering) component of gastric secretory responses, and gastric emptying, and the release of glucagon. Capsaicin prevented the indomethacin- and ethanol-induced gastric mucosal damage; meanwhile capsaicin itself enhanced (GTPD). Capsaicin prevented the indomethacin-induced gastric mucosal microbleeding. The expression of TRVP1 and CGRP increased in the gastric mucosa of patients with chronic gastritis (independently of the presence of Helicobacter pylori infection), and the successfully carried out eradication treatment. The human first phase examinations (the application of acetylsalicylic acid (ASA), diclofenac, and naproxen together with capcaicinoids) (given in doses that stimulate capsaicin-sensitive afferent vagal nerves) showed no change in the pharmacokinetic parameters of ASA and diclofenac and the ASA and diclofenac-induced platelet aggregation. Conclusions: Capsaicin represents a new orally applicable gastroprotective agent in healthy human subjects and in patients with different chemical and Helicobacter pylori-induced mucosal damage and in many other diseases requiring treatment with NSAIDs.