Background: Potential of hepatocyte growth factor (HGF)- stimulating signaling pathways related to cytotoxin-associated gene A (CagA) to predict gastric cancer development has not been fully investigated. Methods: We conducted a nested case-control study consisting of 238 gastric cancer cases and 238 matched controls within the Korean Multicenter Cancer Cohort. Plasma HGF concentrations were measured with a human HGF ELISA. Odds ratios (OR) and 95% confidence intervals (CI) for gastric cancer development according to HGF level were calculated using conditional logistic regression model. Results: Sequential elevation of gastric cancer risk according to HGFlevel increase was observed (OR, 10.99; 95% CI, 4.91-24.62) for highest quartile HGF (≥364 pg/mL) versus lowest quartile HGF (<167 pg/mL). A significantly increased gastric cancer risk associated with high HGF level measured even 6 or more years prior to cancer diagnosis was also found. The group with both high risk of HGF and CagA-related genetic variants was associated with highest gastric cancer risk compared with the group with both low risk of HGF and genetic variants (Pinteraction = 0.05). Model performance usingHGFand CagA-related genetic variants to discriminate gastric cancer was fair [area under the curve of receiver operating characteristic (AUC-ROC), 0.71; 95% CI, 0.64-0.78] and significantly higher than that of model not including those biomarkers. Conclusions: Our results suggest HGF as a potential biomarker to predict gastric cancer development. Impact: These findings suggest HGF as a useful biomarker to predict gastric cancer risk. Further research to assess gastric cancer risk based on useful biomarkers, including HGF, may contribute to primary prevention of gastric cancer.