Clinical differentiation between cystic lesions of endodontic and non-endodontic origin is of importance because correct diagnosis may affect treatment decision making. Most radicular cysts are treated with conservative approaches and, therefore, are not surgically removed. The objective of this study was to determine the accuracy of clinical diagnosis of periapical lesions as compared to the histological findings, and to evaluate various associated factors. All biopsy specimens submitted for histological evaluation from 2002 to 2009 were assessed. Only cases of periapical lesions with complete patient data and clinical diagnosis were included. Sensitivity, specificity and accuracy of the clinical diagnosis were calculated and various patient-related factors were evaluated. Of the 4,908 cases, 183 met inclusion criteria. Histologically, there were 171 lesions of radicular cysts and 12 cases of non-endodontic cysts, including OKC and Incisive Canal Cyst. The diagnostic accuracy for clinical diagnosis for radicular cysts was 91.84% and 91.84% for non-endodontic cysts. There was a high accuracy of clinical differentiation between cystic lesions of endodontic and non-endodontic origin. However, some non-endodontic lesions may be incorrectly diagnosed clinically as lesions of endodontic origin. Histological evaluation may be necessary for the correct diagnosis. Further clinical studies are needed to evaluate clinical examination and histological diagnosis of periapical lesions.