This study compared the differential diagnosis of large periapical lesions (granuloma versus cyst) to traditional biopsy using Cone Beam Computed Tomography (CBCT), the NewTom 3G. Large lesions were scanned and a preoperative diagnosis based on gray value measurements of the imaged lesion area was made. After surgery a biopsy report was obtained and compared to the CBCT diagnosis. In 13 out of 17 cases, the diagnosis coincided. In 4 out of 17 cases, the CBCT read cyst with the oral pathologist's diagnosis being granuloma. Thus, the CBCT may provide a more accurate diagnosis than biopsy and histology providing a diagnosis without invasive surgery and/or waiting a year to see if nonsurgical therapy is effective.