Background and Objective: Esophageal cancer especially squamous cell carcinoma (SCC) is one of the most common gastro intestinal malignancies in north part of Iran (Khorasan). The standard treatment for esophageal cancer is surgical resection, but its outcome remains poor. Then, the oncologists try to treat this cancer with sandwich protocols especially neo-adjuvant chemo-radiotherapy. Several studies have reported that over expression of Cyclin D1 is a negative prognostic factor and is correlated with poor response to chemo-radiotherapy and decrease of survival. For this reason we evaluated Cyclin D1 expression in patients with esophageal SCC and its effect on response rate to neo- adjuvant chemo-radiotherapy in north-east Iran. Materials and Methods: We analyzed Cyclin D1 expression by immunohistochemistry in 37 endoscopic biopsies of esophageal SCC from April 2004 to March 2005 in Mashhad University of Medical Science, Iran and compared it with clinical and pathologic response rate to neo adjuvant chemo-radiotherapy. Results: Cyclin D1 over expression was detected in 24 patients (64.9%). Nine patients with Cyclin D1 over expression had pathologic complete response (37.5%) as compared with 9 patients with negative cyclin D1 expression (69.2%) (P=0.09). Conclusion: Cyclin D1 is a useful tumor marker to select patients may not be suitable for neo- adjuvant chemo-radiotherapy and it is better to refer them for surgery or definitive radiotherapy.