The past decade has witnessed a global rise in the prevalence of peptic ulcer disease which is unrelated to non-steroidal anti-inflammatory drugs (NSAIDs) or Helicobacter pylori infection. Although initially recognized in the West, this disease is being increasingly recognized in the Asian population. The higher risk of bleeding and ulcer recurrence in this subgroup of patients highlights the clinical importance of analyzing the changing trends of peptic ulcer disease in developing countries. To assess the proportion of non-NSAID, non-H. pylori peptic ulcer disease in an Indian cohort of patients with peptic ulcer disease managed at a tertiary care center; and to compare the gastric and duodenal ulcer subgroups in these patients. Patients diagnosed with peptic ulcer disease were screened for a history of NSAID use and those with a negative history were tested for H. pylori using a combination of rapid urease test (RUT) and (14)C-urea breath test (UBT). Only those cases which tested negative for both the tests were considered 'H. pylori-negative'. Serum gastrin was measured in all patients included in the study. Seventy-four gastric ulcer (GU) and 54 duodenal ulcer (DU) patients with no history of NSAID use were enrolled. Of these, 36 GU (45.9%) and 16 DU (29.6%) patients were H. pylori-negative. The proportion of non-NSAID non-H. pylori gastric ulcers was significantly higher than duodenal ulcers (p < 0.05). However, patients who tested negative for H. pylori did not differ significantly from those who tested positive with regard to age, gender, serum gastrin level, and presence of risk factors, like smoking and alcoholism. The current study indicates existence of high proportion of non-NSAID, non-H. pylori peptic ulcer disease in Indian patients.