This retrospective study ascertained the incidence and clinicopathologic features of central giant cell granulomas (CGCGs) associated with teeth with necrotic pulps or teeth that had received previous endodontic treatment and determined whether periapical CGCGs can result in endodontic misdiagnosis. Clinical and histopathologic data of biopsy specimens diagnosed as CGCG were collected from the archives of the Oral Pathology Laboratory, Temple University, and were reviewed. Over the 9-year period, 16 of 79 cases (20%) of CGCG were associated with a tooth that had a history of pulp necrosis. Of those, 14 (88%) were associated with previous root canal treatment. The data from this series of 79 cases of CGCG also showed that CGCGs were less common in women, less common before age 30, and did not cross the midline of the jaw as often as previously reported. Clinical and histopathologic data were compared from (1) CGCGs associated with teeth with vital pulps or that occurred in edentulous areas; (2) CGCGs associated with teeth with necrotic pulps; and (3) 194 cases of periapical granulomas and radicular cysts. These data strongly suggest that CGCGs associated with teeth with necrotic pulps are not directly related to periapical inflammation and may be misdiagnosed as endodontic lesions. Posttreatment follow-up and routine submission of periapical surgical specimens are emphasized.