Introduction: Radicular cysts (RCs) and residual radicular cysts (RRCs) are the sequelae of dental caries and that leads to proliferation of epithelial rests of Malassez in periapical tissues. Objectives:The aim was to evaluate the relationship between Langerhans cells, macrophages, matrix metalloproteinases (MMP-9, MMP-13), and tumor necrosis factor-alpha (TNF-α) in the capsule and lining epithelium of cystic lesions.Materials and Methods: Twenty RCs and 20 RRCs were submitted to immunohistochemical analysis with anti-CD68, anti-CD1a, anti-MMP-9, anti-MMP-13, and anti-TNF-α antibodies. The Mann-Whitney test and the Spearman correlation test were used for analysis of the data (P < 0.05). Results:The immunoexpression of MMP-13 and CD68 was significantly higher in RCs when compared with RRCs (P = 0.011 and 0.012, respectively). The presence of an intense inflammatory infiltrate was significantly correlated with the immunoexpression of CD68 in RCs (P = 0.025). Expression of CD68 showed a significant positive correlation with MMP-13 (P = 0.015). A moderate correlation was observed between MMP-9 and MMP-13 (P = 0.010). TNF-α expression was more common in RCs (P = 0.001). CD1a was more frequently expressed in atrophic epithelium (P = 0.041) and was significantly correlated with TNF-α (P = 0.014). Conclusion:Langerhans cells induce a greater release of TNF-α which, in turn, is responsible for the stimulation of M1 macrophages. Higher immunoexpression of MMP-13 and MMP-9 is observed in the early stages of RCs compared with RRCs. Therefore, the toxins of microorganisms present in highly inflamed RCs are the main factors triggering a proinflammatory immune response and greater cystic expansion in the early stages of these lesions.