Many diseases of the upper gastrointestinal tract developed in patients with Helicobacter pylori (H. pylori) infection, thus the conditions unrelated to H. pylori are rare. Here, we described the therapeutic trends of diseases in H. pylori negative individuals. Proton pump inhibitor (PPI) is superior to H2 receptor antagonist in both gastroesohageal reflux disease (GERD) including reflux esophagitis and non-erosive reflux disease (NERD) whereas therapeutic gains of PPI treatment for NERD patients are lower than those reported in GERD because of heterogeneity of NERD pathophysiology. Endoscopic therapy for PPI refractory GERD patients remains to be established because there are few studies concerning the effectiveness or safety of the procedures. Main cause of H. pylori-negative ulcer diseases is the use of non-steroidal anti-inflammatory drugs (NSAIDs). PPI therapy is effective for both the prevention and treatment of NSAIDs-induced peptic ulcer. Considerations that should be entertained as causes of intractable peptic ulcers include Zollinger-Ellison syndrome or Crohn's disease. Gastric cancer and carcinoid tumor should be treated with endoscopic or surgical resection regardless of H. pylori infection. As for the treatment for gastric H. pylori-negative MALT lymphoma, radiation therapy (RT) should be selected first, and next chemotherapy will be given to the patients who failed to RT.