Odontogenic keratocysts manifest themselves as radiolucencies that can appear anywhere in the maxilla or mandible, including periradicular areas; they may thus masquerade as lesions of endodontic origin. This retrospective study examined 239 odontogenic keratocysts received by the Oral Pathology Laboratory at Temple University School of Medicine over a 3-year period. Twenty-one (9%) of the cysts received were located periradicularly; of these 21, 12 (57%) were associated with nonvital or endodontically treated teeth and thus mimicked lesions of endodontic origin. Because of its aggressive nature and tendency to recur, the periradicular odontogenic keratocyst should be included in the differential diagnosis of lesions that are refractory to endodontic treatment.