Several risk factors including environmental factor, Genetic and nutritional deficiencies have been associated with Esophageal Cancer (EC) in high risk areas. In a case-control association study, the association of HLA class I and esophageal carcinoma has been investigated. A total number of 30 patients and 30 clinical healthy individuals matched for sex and age with the same ethnicity and residence status were enrolled. Five milliliter defibrinated blood taken from each individual and diluted 1:1 with Hanks balanced salt solution buffer. The diluted blood added to 3.0 mL separating medium (ficol hypaqe). Lymphocyte separated and HLA, A, B and C molecules were determined by using the Terrasaki Mirocytotoxicity test. Data were analyzed by Chi square and Fisher exact tests. Thirty patients (20 females and 10 males) with age 61 +/- 2.4 enrolled in this study. Only patients with definite diagnosis of Squamous Cell Carcinoma (SCC) included and Patients with other esophageal cancer (adenocarcinoma) excluded. The frequency of many HLA molecules were different in comparison of patients and control groups, but statistical analysis of the data revealed that only difference between frequency of HLA A11, B41 and Cw3 are significant (p<0.05). We concluded that HLA-A11, -B41 and -Cw3 molecules may be risk factors for esophageal cancer in northern part of Iran.