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To identify the risk of gastric cancer in first-degree relatives of gastric cancer patients, and to determine if there is an interaction between Helicobacter pylori (H. pylori) infection and family history of gastric cancer in gastric carcinogenesis.It is unclear to what degree a family history of gastric cancer is associated with stomach cancer risk in Korea.From May 2003 to July 2008, 428 gastric cancer patients and 368 controls were included in the analyses. Logistic regression models including age, sex, family history of gastric cancer, residency during childhood, smoking, monthly income, spicy food diet and H. pylori status were evaluated to estimate the odds ratios (ORs) of developing gastric cancer.Adjusted OR for gastric cancer increased 3-fold for subjects reporting first-degree relatives with gastric cancer [OR 2.85, 95% confidence interval (CI): 1.83-4.46]. The association was strong in the 40 to 59 years age group (OR 4.00, 95% CI: 2.06-7.76), and became weaker in subjects older than 60 years of age (OR 1.81, 95% CI: 0.95-3.46). Compared with the uninfected subjects without a family history, subjects with both a family history and H. pylori infection had a 5-fold increased risk (OR 5.32, 95% CI: 2.76-10.25).After adjusting for environmental factors and H. pylori infection, a family history of gastric cancer remained independently associated with gastric cancer. The interaction between H. pylori infection and family history of gastric cancer might be a rationale for H. pylori eradication in the gastric cancer relatives as a strategy to prevent gastric cancer.