The aim of this study was to analyze the presence of myofibroblasts and matrix metalloproteinase 2 (MMP-2) in radicular cysts (RCs), dentigerous cysts (DCs), and keratocystic odontogenic tumors (KOTs).For the study, 29 RCs, 19 DCs, and 15 KOTs were selected. Immunohistochemical reactions were performed by using anti–MMP-2 and anti–α-smooth muscle actin (SMA) antibodies. For the analysis, 10 high-power fields were observed in each case to determine the percentage of positive cells, which was classified as negative, weak, or strong.The presence of myofibroblasts (α-SMA–positive cells) was most common in KOTs (46.67%), followed by DCs (36.84%) and RCs (31.04%); however, it was not statistically significant (P = .8). The stromal MMP-2 expression was positive in all lesions but 1 case of KOT. Most cases of RC and DC presented strong MMP-2 expression in the stroma, whereas half of the KOTs showed similar classification. The MMP-2 expression was commonly found in the epithelial lining of the lesions; it was strong in almost all KOTs. No correlation between epithelial and stromal MMP-2 and α-SMA expressions was observed.Myofibroblasts and MMP-2 are frequent in RCs, DCs, and KOTs and eventually can contribute to bone resorption, favoring the progression and growth of these lesions.