OBJECTIVE: To elucidate the histopathological, immunohistochemical, and ultrastructural characteristics of a large series of calcifying odontogenic cysts (COCs). STUDY DESIGN: This was a multicenter cross-sectional retrospective study of seven oral pathology department laboratories from four countries. Clinical, demographic, and radiographic data of the patients were collected. Histopathological, immunohistochemical, and microstructural analyses were based on formalin-fixed, paraffin-embedded tissues. All variables were described, and associations were analyzed using Pearson's chi-square and Fisher's exact tests. RESULTS: A total of 146 cases of COC were analyzed, including 141 central and 5 peripheral cases. Male patients were most involved, with a mean age of 27.8 years. The main clinical presentation was an asymptomatic swelling in the anterior maxilla. Radiographically, most cases appeared as a single well-defined unilocular radiolucency. Forty cases of COC were associated with other odontogenic lesions, including odontoma, ameloblastic fibroma, and odontogenic keratocyst. Immunohistochemical study showed cytoplasmic positivity for CK AE1/AE3, CK14, CK19, and Bcl-2 protein. Nuclear expression of β-catenin was observed in most cases. CONCLUSIONS: COC mainly affects adult males between the second and third decades of life. Asymptomatic maxillary swellings with diverse radiographic and histopathological presentations were noted. Moreover, COC may present associations with other odontogenic lesions, particularly odontomas in younger patients.