Gastric cancer is one of the most common malignancies worldwide. In this study, we screened for genes upregulated in gastric cancer by comparing gene expression profiles from serial analysis of gene expression and microarray and identified the palate, lung, and nasal epithelium carcinoma-associated protein (PLUNC) gene. Immunostaining for PLUNC in 140 gastric cancer cases revealed strong and extensive staining of PLUNC in hepatoid adenocarcinoma of the stomach, whereas 7% of conventional gastric cancer cases showed focal immunostaining of PLUNC. Gastric hepatoid adenocarcinoma is an extrahepatic tumor characterized by morphologic similarities to hepatocellular carcinoma. To investigate the utility of PLUNC immunostaining in the diagnosis of gastric hepatoid adenocarcinoma, six cases of gastric hepatoid adenocarcinoma (six primary tumors and two associated liver metastases) were studied further. PLUNC staining was observed in all six primary hepatoid adenocarcinomas. PLUNC staining was observed in both the hepatoid adenocarcinoma and tubular/papillary adenocarcinoma components of primary tumors, although PLUNC staining was preferentially localized in tubular/papillary adenocarcinoma components. Staining of PLUNC was also detected in both liver metastases. PLUNC staining was not observed in 52 cases of primary hepatocellular carcinoma or in normal adult or fetal liver. These results indicate that PLUNC is a novel marker that distinguishes gastric hepatoid adenocarcinoma from primary hepatocellular carcinoma.