Herein, we describe the identification of GPCR56, an orphan G-protein coupled receptor, to be differentially expressed in esophageal squamous cell carcinoma. Although, GPCRs have been demonstrated to be altered in various human cancers, much is still unknown about GPCR56 expression in tumors. To evaluate the expression of these genes in esophageal tissues, we performed semi-quantitative Reverse-Transcription Polymerase Chain Reaction in ESCCs, dysplasia and matched normal esophageal epithelium. Increased transcript levels of GPCR56 were detected in 48% of ESCCs, while the adjacent non-malignant esophageal tissue did not show the expression of this transcript. Interestingly, most of the dysplastic tissues analyzed also exhibited increased expression of GPCR56 suggesting that alteration in GPCR56 expression is an early event in esophageal tumorigenesis. In depth analysis of GPCR56 in different stages of development and progression of esophageal tumorigenesis is warranted to explore its utility as potential early diagnostic marker and its function in esophageal cancer.