Abstract Introduction Cysts and granulomas are chronic periapical lesions mediated by a set of inflammatory mediators that develop to contain a periapical infection. This study analyzed the nature of the inflammatory infiltrate, presence of mast cells, and in situ expression of cytokines (interleukin IL-17 and transforming growth factor TGF-ß), chemokines (macrophage inflammatory protein MIP-1ß and monocyte chemotactic protein MCP-1), and nuclear transcription factor (FoxP3) in human periapical granulomas and cysts compared with a control group. Methods Fifty-five lesions (25 periapical cysts, 25 periapical granulomas, and 5 controls) were analyzed. The type of inflammatory infiltrate was evaluated by hematoxylin-eosin 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. Results The inflammatory infiltrate mainly consisted of mononuclear cells. In cysts, mononuclear infiltrates were significantly more frequent than mixed (polymorphonuclear/mononuclear) infiltrates ( P = .04). Mixed inflammatory infiltrates were significantly more frequent in patients with sinus tract ( P = .0001). The number of mast cells was significantly higher in granulomas than in cystic lesions ( P = .02). A significant difference in the expression of IL-17 ( P = .001) and TGF-ß ( P = .003) was observed between cysts and granulomas and the control group. Significantly higher IL-17 levels were also observed in cases of patients with sinus tract ( P = .03). Conclusions We observed that chronic periapical lesions might experience a reagudization process that is correlated with an increased leukocyte infiltration, with the predominance of neutrophils attracted by a chemokine milieu, as well as the increased presence of IL-17.