Background: Unicystic ameloblastoma arises from similar tissues as the odontogenic cysts. It may also arise from the epithelial lining of these cysts. Furthermore, the epithelial lining of unicystic ameloblastoma is variable and may be almost completely nondescript, which may lead to diagnostic confusion with odontogenic cysts. Calretinin is a calcium-binding protein that has been suggested to be a specific immunohistochemical marker for ameloblastic tissues. The aim of this study was to investigate the usefulness of calretinin in the differentiating unicystic ameloblastoma from odontogenic keratocyst, dentigerous cyst and radicular cyst of the jaws. Materials and Methods: Formalin-fixed, paraffin embedded tissue blocks of 23 unicystic ameloblastomas, 6 odontogenic keratocysts, 8 dentigerous cysts and 10 radicular cysts were utilized. Five micrometer thick sections were made from the tissue blocks and mounted on silanized glass slides. Immunohistochemical staining was done using a 1:100 dilution of mouse monoclonal anti-calretinin primary antibodies (Abcam, SA;Clone 1F5H1) and incubating overnight at 4°C. The staining reaction was visualised using diaminobenzidine substrate solution. Stained tissue sections were evaluated for the presence, distribution, and intensity of staining of the immunoreactive cells. Data analysis was done using SPSS version 23. Statistical tests employed were Chi square test and Kruskal-Wallis test. The level of significance was set at 95% (p-value Results: Calretinin expression was seen in 14 (60.9%) cases of unicystic ameloblastoma, 3 (50.0%) cases of odontogenic keratocyst and a lone (12.5%) case of dentigerous cyst. None of the 10 cases of radicular cyst showed positive expression of calretinin. Staining in unicystic ameloblastoma was mostly localized to the superficial layers, whereas in odontogenic keratocyst it involved all layers of the epithelial lining. There was significant association between lesion type and the immunohistochemical expression of calretinin (p = 0.003). The