The first and most important action on encountering a patient with unexplained gastric or duodenal ulceration is to double check that they are truly H. pylori negative and also not taking any ulcerogenic medicines. Once the patient is confirmed to be H. pylori negative and NSAID negative, ensure that biopsies of the ulcer-whether gastric or duodenal-and of the surrounding gastric and duodenal mucosa are obtained to exclude underlying malignancy/lymphoma, Crohn's disease, and unusual infectious agents. If the etiology of the ulceration remains unexplained, an underlying gastrinoma should be considered and excluded. Patients with idiopathic ulcers should be maintained on proton pump inhibitor therapy, and higher doses may be required to control acid secretion and prevent ulcer relapse in these H. pylori-uninfected subjects.