Abstract Cysts and granulomas are chronic periapical lesions mediated by a set of inflammatory mediators that develop in order to contain a periapical infection. This study analyzed the inflammatory infiltrate, mast cells and in situ expression of cytokines, chemokines and FoxP3 in human periapical granulomas and cysts compared to controls. Fifty-five lesions (25 cysts, 25 granulomas and 5 controls) were analyzed. The type of inflammatory infiltrate was evaluated by HE staining and the presence of mast cells was analyzed by toluidine blue staining. Indirect immunohistochemistry was used to evaluate the expression of cytokines, chemokines and FoxP3. The inflammatory infiltrate mainly consisted of mononuclear cells. In cysts, mononuclear infiltrates were significantly more frequent than mixed (polymorphonuclear/mononuclear) infiltrates (p=0.04). Mixed inflammatory infiltrates were significantly more frequent in patients presenting fistulae (p=0.0001). The number of mast cells was significantly higher in granulomas than in cystic lesions (p=0.02). A significant difference in the expression of IL-17 (p=0.001) and TGF-β (p=0.003) was observed between cysts and granulomas and the control group. Significantly higher IL-17 levels were also observed in cases of patients with fistulae (p=0.03). Mast cells, TGF-β and IL-17 probably participate in the modulation of the inflammatory process in established periapical lesions, especially in granulomas.