The purpose of this study was to evaluate the suitability of a digital radiograph registration and subtraction software for a sensitive and reliable assessment of the progress of chronic apical periodontitis. Ninety cases of teeth with chronic apical periodontitis have been studied. In each case, a preoperative radiograph was taken, root canals were prepared, and a Ca(OH)2 paste was placed in the root canals. Radiographic control and replacement of Ca(OH)2 paste took place at 15-day intervals. The root canals were obturated 1.5 months after the first appointment. Recall radiographs were taken 0.5, 1.5, 3, 6, and 12 months after the obturation. All radiographs were taken for each case under constant conditions by using a direct digital radiography system. In each case, the preoperative, postoperative, and control and recall radiographs were digitally registered and pairwise subtracted. The resulting images were further processed by using contrast enhancement and pseudocoloring methods. Changes to the periapical tissue structure were easily detectable by using the above-mentioned methodology, even during short time intervals.