The receptor activator of nuclear factor kappa B (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system is important in osteoclastogenesis and may play a role in the development of apical periodontitis. This immunohistochemical study evaluated the distribution of the expression of these regulators of bone resorption in periradicular cysts. Biopsy specimens from 40 consecutive periradicular cysts registered in the files of the Oral Pathology Laboratory were selected for the study on the basis of an initial analysis of archived histopathologic slides. Sections were stained with hematoxylin-eosin for preliminary analysis, and then silanized slides were used for immunohistochemical reactions with anti-RANK, anti-RANKL, and anti-OPG antibodies by the immunoperoxidase technique. The expression of these molecules in different tissue compartments and in the inflammatory infiltrate of cysts was compared. Analysis of the distribution of each marker in different areas of the cyst revealed no significant difference in the expression of RANK, RANKL, or OPG in areas of normal epithelium when compared with areas of hyperplastic epithelium. As for the connective tissue, higher expression of both RANK (P < .05) and RANKL (P < .05), but not OPG, was observed in the chronic inflammatory infiltrate, in comparison with the acute infiltrate. When the expression of the 3 molecules was compared per area of the cystic lesion, higher expression of RANK in comparison with OPG was verified in the areas of both normal and hyperplastic epithelium. RANKL was also significantly more expressed in the normal epithelium than OPG (P < .05). In the connective tissue, RANK expression was higher than OPG in both chronic and mixed infiltrates (P < .05) and also higher than RANKL expression in mixed infiltrate (P < .05). RANKL expression in chronic infiltrate was higher in comparison with OPG expression (P < .05). The results demonstrated that the type of inflammatory infiltrate present in periradicular cysts appears to influence the expression of RANK, RANKL, and OPG. The chronic infiltrate is likely to have increased osteolytic activity because of a higher RANKL/OPG ratio.