A previous study showed that the ferret canine is an appropriate model for inducing periapical lesions. Ferret canines were used in this study to study changes in periapical lesions after root canal treatment (RCT). After periapical pathosis was induced in the maxillary and mandibular canines of six ferrets, RCT was performed on three of the four canines in each animal. Each ferret received periodic intraperitoneal injections of Procion red dye. Two animals were killed at each of 4, 8, and 12 wk after RCT. Apices and surrounding lesions were evaluated radiographically, histologically, and by fluorescent microscopy. Periapical radiolucencies increased in size during induction but showed no changes after RCT. Lesions in untreated teeth showed features of granulomatous inflammation, mainly the presence of macrophages and lymphocytes. After RCT, there was histological evidence of healing in the form of cementum deposition, increased vascularity, and increased fibroblastic and osteoblastic activity. Fluorescent staining showed cementum deposition of variable thickness in the treated specimens.