Objective. To determine the frequency with which histopathologic examination of periapical biopsy specimens contributed information not anticipated clinically. Study design. Clinical and histopathologic information from 805 sequentially submitted periapical biopsy specimens over a 2-year period was compared. Clinical data included endodontic status, age and sex of patient, location of lesion, and submitting clinician. Histopathologic diagnoses were categorized as 1) sequelae of pulpal necrosis (SPN), 2) complicated SPN (CSPN) with infection or antral involvement, or 3) periapical lesions unrelated to pulpal necrosis (PLUPN). Results. Of the 805 cases, 788 (97.9%) were SPN, 9 (1.1%) were CSPN, and 8 (1%) were PLUPN, representing a range of locally aggressive but benign lesions and 1 malignancy. Comparison of clinical and histologic diagnoses indicated that the clinical interpretation was inaccurate in 4.1% of cases (suggesting SPN in PLUPN cases or PLUPN in SPN cases). In another 0.9% of cases, the histologic analysis (indicating CSPN) contributed additional information to the clinical diagnosis. Conclusions. A histopathologic examination contributed clinically relevant information in 5.0% of submitted cases. General extrapolation of this figure is not possible. Theoretical considerations, which could positively or negatively bias this figure, are discussed.