Abstract Abundant in vitro and animal studies have shown a protective effect of green tea against various types of cancer, but the evidence from epidemiologic studies is inconclusive. In this nested case-control study, we used plasma biomarkers to directly investigate the effect of tea polyphenols on the risk of gastric cancer. Subjects were followed up from 1990 to 2004. Among 36,745 subjects who answered the baseline questionnaire and provided blood samples, 494 gastric cancer cases matched to 494 controls were used in the analysis. The validated method used high-performance liquid chromatography to analyze baseline plasma samples. For men, a high plasma level of (-)-epigallocatechin was associated with an increased risk of gastric cancer. For women, a high plasma level of (-)-epicatechin-3-gallate (ECG) was associated with a decreased risk of gastric cancer; the adjusted odds ratios (95% confidence intervals) for ECG levels 0.32 to 9.2 and 9.3+ ng/mL were 1.03 (0.41-2.59) and 0.25 (0.08-0.73), respectively, compared with those whose ECG level was under the detection limit (P for trend = 0.02). Cigarette smoking was suggested to play a role as an effect modifier, which explains in part the different patterns observed by gender. (Cancer Epidemiol Biomarkers Prev 2008;17(2):343–51)