The aim of the study was to analyze the expression of Cdx2 and nuclear PTEN in relation to clinicopathological features of gastric cancer tissue biopsies in order to determine the value of a combined analysis of Cdx2 and nuclear PTEN expression in distinguishing histological types and prognosis of gastric cancers. The expression of Cdx2 and nuclear PTEN was studied using immunohistochemistry of paraffin-embedded tumor specimens from 99 patients who underwent radical D2 gastrectomy between 1999 and 2001. Cdx2 and nuclear PTEN expression were detected in 39.6% (36 of 91) and 70.3% (64 of 91) of gastric cancer cases, respectively. There was a negative correlation between Cdx2 expression and Lauren classification (p=0.032), and between nuclear PTEN expression and lymph node metastasis (p=0.049). Patients with Cdx2-positive, or nuclear PTEN-positive expression had higher survival rates than those with Cdx2-negative or nuclear PTEN-negative expression (p<0.001 and p=0.003, respectively). Co-expression of Cdx2 and nuclear PTEN showed significantly lower levels in diffuse- or mixed-type cancers than in intestinal-type cancers (p=0.005). Multivariate analysis revealed that Cdx2 expression was an independent prognostic indicator of gastric cancer (p=0.014). These data suggest that combined analysis of Cdx2 and nuclear PTEN expression can have significant value in distinguishing histological types of gastric cancer and assessing prognosis in patients with gastric cancer.