The experiment was undertaken to observe the correlation between the expression of c-Fos and osteoclasts in experimental periapical lesions in rats. Apical periodontitis was induced in Wistar rats by occlusal exposure of the pulp of their mandibular first molars. After the exposure, 25 Wistar rats were killed on days 0, 7, 14, 21, and 28. The jaws that contained the first molar were obtained and routinely prepared for immunohistochemistry and enzyme histochemistry. A few c-Fos-positive cells and osteoclasts could be observed on day 7, and both climaxed on day 14. In the 21-day and 28-day samples, the expression of c-Fos decreased, and fewer osteoclasts could be observed. From day 7 to day 28, a significant positive correlation was found between the expression of c-Fos and osteoclasts. These findings demonstrated that c-Fos might be associated with the differentiation of osteoclasts in the periapical lesions.