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. Periapical lesions are most commonly of endodontic origin and related to pulp infection 1,2. Bacteria and their by-products can exit the root canal system through the apical foramen and cause an inflammatory response in the periapical tissues 3-5 and resorption of the alveolar bone surrounding the root 6. Most lesions of endodontic origin can be classified as periapical granuloma or radicular cyst 7-12. The reported prevalence of radicular cysts within periapical lesions varies between 6 and 55% and of periapical granulomas ranges between 46 and 84% 7-13. The most of the cysts in the jaws develop from odontogenic epithelium and classified as inflammatory and developmental 14-16. The origin of the inflammatory cysts are the epithelial rests of Malassez. The bacterial byproducts from the contaminated necrotic pulp may stimulate the proliferation of these epithelial rests and lead to the formation of a radicular cyst 3,4,10,17. Radicular cysts are the most common cysts found in the jaws. Their epithelial lining may demonstrate varying degrees of inflammation; additionally, cholesterol crystals and fibrosis may be found in the cystic cavity 10,13,18. Among the cysts of the developmental origin are Dentigerous cysts and Keratocystic Odontogenic Tumor (KCOT). Dentigerous cysts are commonly found in children from 2 to 14 years. KCOT are often found in the posterior mandible. They are considered aggressive and have a higher recurrence rate relatively to the other odontogenic cysts 19 , and require surgical treatment. Determination of the cysts' nature ...