To further understand the involvement of Notch pathway signaling in the pathogenesis of periapical cyst the immunohistochemical expression of Notch-1 and Notch-2 receptors, Jagged-1 ligand, and HERP-1 transcription factor in the lining epithelium of periapical cysts was investigated. Thirty human periapical cysts were immunohistochemically stained with antibodies against Notch-1, Notch-2, Jagged-1, and HERP-1. Epithelial expression of each antibody was correlated with the presence of inflammation in the connective tissue of the cystic wall. Notch-1 was identified in the basal and suprabasal epithelial cells of 30/30, Notch-2 in 19/24, and Jagged-1 in 27/30 cysts. HERP-1 was detected in scattered subepithelial inflammatory cells, but not in the lining epithelium of cysts. There was no significant correlation between the immunohistochemical expression of each antibody and the presence of inflammation in the connective tissue of the cystic wall. This immunohistochemical study showed expression of Notch-1/2 and Jagged-1 in periapical cysts that combined with the expression of HES1/5 found in a previous report, are indicative of the activation of Notch an endocrine-paracrine mechanism. Further research on the activity of Notch and other pathways in periapical cysts may contribute both to elucidate their pathogenesis and select molecular targets for future novel treatments. Key words:Odontogenic cyst, radicular cyst, etiology, epithelial cells, Notch, Jagged, HERP.