Gastric carcinogenesis may be under the combined influence of factors related to the host, Helicobacter pylori bacterial virulence and the environment. One possible host-related factor is the inflammatory or immune response. To clarify this point, we investigated the association between plasma levels of C-reactive protein (CRP) and serum amyloid A (SAA) and the subsequent risk of gastric cancer in a population-based nested case-control study. Subjects were observed from 1990 to 2004. Among 36 745 subjects who answered the baseline questionnaire and provided blood samples, 494 gastric cancer cases were identified and matched to 494 controls for our analysis. The overall distribution of CRP and SAA was not apparently associated with the development of gastric cancer. However, a statistically significant increased risk was observed when subjects were categorized dichotomously. The adjusted odds ratio (OR) for the development of gastric cancer for the CRP-positive group (CRP > 0.18 mg/dl) compared with the CRP-negative group was 1.90 [95% confidence interval (CI): 1.19-3.02, P = 0.007]. The OR for the SAA-positive group (SAA > 8 mug/ml) compared with the SAA-negative group was 1.93 (95% CI: 1.22-3.07, P = 0.005). In conclusion, our results suggest that those who react strongly to inflammation or who have a high host immune response, as reflected by extremely elevated plasma levels of CRP and SAA, are at a high risk to develop gastric cancer.