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Periapical cysts and granulomas are chronic lesions caused by an inflammatory immune response against microbial challenge in the root canal. Different cell types, cytokines, and molecules have been associated with periapical lesion formation and expansion. Therefore, because of the chronic inflammatory state of these lesions, the aim of this study was to evaluate the in situ expression of matrix metalloproteinase (MMP)-14 and -19, tissue inhibitor of metalloproteinase (TIMP)-3 and -4, CD68, and inducible nitric oxide synthase (iNOS) in periapical cysts and granulomas.Sixteen cases of periapical cysts and 15 cases of periapical granulomas were analyzed. Ten normal dental pulps were used as the negative control. Immunohistochemistry was performed with anti–MMP-19, anti–MMP-14, anti–TIMP-3, anti–TIMP-4, anti-iNOS, and anti-CD68 antibodies.The expression of TIMP-3, TIMP-4, iNOS, and CD68 was significantly higher in both the cyst and granuloma groups than in the control group. TIMP-4 was also significantly higher in cases of chronic apical abscess. There was also a significant difference in the expression of MMP-14 between the cyst and control groups. However, there were no differences in the expression of MMP-19 between the 3 groups.Our data suggest that the expression of MMP-14, TIMP-3, and TIMP-4 is associated with the development of periapical lesions.The expression of TIMP-3, TIMP-4, iNOS, and CD68 was significantly higher in cysts and granulomas than in the control group.TIMP-4 was also significantly higher in cases of reacutization.The data presented here suggest that the expression of MMP14, TIMP-3, and TIMP-4 is associated with the development of periapical lesions.