Submucosal cysts (SMCs) might result from severe gastritis and be related to gastric carcinogenesis, although direct evidence is limited. We studied clinicopathologic findings for gastric cancers arising in mucosa with SMC and the relation to gastritis. In 504 submucosal invasive cancer cases, SMC was found in 100. Comparison of degrees of gastritis using the Updated Sydney system, thickness of muscularis mucosae, and the patients' smoking and drinking habits and obesity showed significant variation between cases of cancer with and without SMC. In the stomach with SMCs, cancers were predominantly differentiated-type adenocarcinomas in men and showed a significant tendency for location in the upper gastric region. Intestinal metaplasia was significantly more severe and the muscularis mucosae were thicker in cancer cases with SMC in comparison with cases without SMC and control cases of gastrointestinal stromal tumor (GIST). Atrophy was also significantly more severe in cancer cases with and without SMC than in cases of GIST. The Brinkman index was also significantly higher. Cases of gastric cancer with SMC show characteristic clinicopathologic features, and SMC formation may be caused by gastritis and influenced by smoking.