Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracilleucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer. (Cancer Sci 2013; 104: 590-598) G astric cancer is one of the most common malignancies and remains the second most frequent cause of cancerrelated death worldwide. Despite recent advances in surgical techniques and medical treatment, the 5-year survival rate for gastric cancer patients is <30%.(1) Investigation of biomarkers for screening at an early curative stage would have great clinical value. Moreover, a large percentage of cancer patients are treated unnecessarily.(2) Biomarkers may be especially useful in the group being more likely to benefit from chemotherapeutics.The MDM2 protein is a negative regulator of the p53 tumor suppressor. The p53 protein functions as a tumor suppressor by inducing the expression of genes that inhibit cell growth and upregulate apoptosis,and its deletion or loss of function is associated with a large fraction of human cancers. (4,5) It has been shown that MDM2 can inhibit p53 bioactivity by blocking the transcriptional activity of p53 and promoting p53 protein degradation.(6) However, p53 can also regulate the synthesis of MDM2.(7) The imbalance of the functions of MDM2 and p53 has been related with several cancers.(8) Molecular epidemiological studies have shown the association between single nucleotide polymorphisms of MDM2 and the risk of various cancers, including ...