Helicobacter pylori infection is a major risk factor for gastric cancer development. Therefore, H. pylori eradication may be an important approach in the prevention of gastric cancer. However, long-term data proving the efficacy of this approach are lacking. This report describes two patients who developed gastric cancer at, respectively, 4 and 14 years after H. pylori eradication therapy. These patients were included in a study cohort of H. pylori-infected subjects who received anti-H. pylori therapy during the early years of development of H. pylori eradication therapy and underwent strict endoscopic follow-up for several years. In both patients, gastric ulcer disease and premalignant gastric lesions, i.e., intestinal metaplasia at baseline and dysplasia during follow-up, were diagnosed before gastric cancer development. These case reports demonstrate that H. pylori eradication does not prevent gastric cancer development in all infected patients after long-term follow-up. In patients with premalignant gastric lesions, in particular in patients with a history of gastric ulcer disease, adequate endoscopic follow-up is essential for early detection of gastric neoplasia.