Recent studies have shown that 70-80% of low-grade mucosa-associated lymphoid tissue (MALT) lymphomas regress in response to eradication of Helicobacter pylori (H. pylori). However, there are no reports on whether gastric high-grade MALT lymphomas regress after H. pylori eradication. We performed H. pylori eradication therapy in 4 patients with stage I, high-grade MALT lymphoma after obtaining their informed consent. H. pylori infection was observed in all 4 patients. The patients were treated with proton-pump inhibitor-based eradication therapy for 1 or 2 weeks, and then underwent endoscopic examination and biopsy sampling. H. pylori eradication was achieved in all 4 patients. Six months after eradication treatment, 2 patients showed complete regression of the lymphoma and 2 patients showed no change. The 2 patients with non-responding lymphoma were then treated with an additional chemotherapy (CHOP regimen), whereupon the tumors completely regressed. These patients, followed-up at least 18 months after eradication treatment, showed no recurrence. We also examined genetic alteration of the p53 and K-ras genes and microsatellite instability in these high-grade MALT lymphomas. One patient with a tumor that showed no change after H. pylori eradication, had a loss of heterozygosity of the p53 gene. No other genetic alterations were detected among the patients. Our results indicate that the eradication of H. pylori may be effective not only for patients with low-grade MALT lymphoma but also for patients with high-grade MALT lymphoma. The treatment may be efficacious as a first-line therapy for patients with high-grade MALT lymphoma. However, our sample size was limited and further studies are needed to clarify the issue.