To clarify the role of calcitonin gene-related peptide (CGRP) in the development of periapical lesions, we examined the distribution of CGRP-immunoreactive (IR) nerve fibers and macrophages, and the behavior of bone tissues in experimentally induced rat periapical lesions by immunohistochemical and quantitative methods. Although no extensive changes were observed at 7 days after pulp exposure, CGRP-IR nerve fibers increased in number until 28 days with a decrease thereafter. These neural changes were closely correlated with the alteration in number of macrophages except on day 7 when macrophages were significantly increased in number as compared with control rats. Tissue repair began to take place and a decrease in number of osteoclasts was observed when the density of CGRP-IR nerve fibers reached a peak. These results suggested that there might be a close relationship between macrophages and CGRP-IR nerve fibers and that CGRP-IR nerve fibers might participate in tissue repair in experimentally induced rat periapical lesions.