MBD4/MED1 is a newly identified mismatch repair gene, which is mutated in colon, endometrial, and pancreatic high-frequency microsatellite instability (MSI-H) tumors. To assess its role in gastric cancers, we investigated MBD4/MED1 mutations in sporadic gastric cancers, compared with colon cancers. Frameshift mutations were found in 29% of gastric and 20% of colon MSI-H cancers, but not in any low-frequency microsatellite instability/microsatellite stable cancers. MBD4/MED1 is mutated in gastric cancers as frequently as in colon cancers; these mutations reduce the accuracy of DNA repair, and may lead to cancer progression.