Background: The tumor related gene profiling in esophageal cancer remains unknown and requires further investigation in order to promote efficient and rapid development of molecular-target agents. The aim of this study was to evaluate the expression level and mutations of tumor related genes in resected esophageal cancer and to assess correlation of the profiling with clinical outcome. Methods: 135 consecutive patients with esophageal cancer who underwent esophagectomy at Shizuoka Cancer Center and Toyama University between October 2002 and November 2011 were analyzed. Protein expression of MET, EGFR, ALK and HGF was determined by Automated QUantification Analysis. Copy number of EGFR, PIK3CA, MET and FGFR1/2 was analyzed by real time PCR. The translocation of ALK gene and mutations of tumor related genes were evaluated by fluorescence in situ hybridisation and TruSeq Amplicon Cancer Panel, respectively. Prognostic factors associated with survival were identified by multivariate analyses using the Cox proportional hazards model. Results: Overall, heavy smoking was significantly associated with high HGF expression (p=0.03938), but was not an independent prognostic factor. After adjustment for clinical features by multivariate Cox regression analysis, high expression of ALK was associated with poor OS in patients without neoadjuvant therapy (HR 4.589, p=0.0102). The translocation of ALK gene was present only in 1 patient. High expression of MET was associated with poor OS in patients with neoadjuvant therapy (HR 5.68, p=0.043). Mutations in p53 and PIK3CA were present in 73% and 13%, respectively. The frequency of mutations in APC, BRAF, ERBB4, VHL, KRAS and EGFR was less than 10%. PIK3CA amplification was observed in 2%. Conclusions: High expression of ALK and MET may be prognostic factors for resected esophageal cancer. Esophageal cancers with high expression level of ALK and MET might be possible candidates for ALK and MET targeting therapies.