The aim of this study was to evaluate the subcutaneous biocompatibility of three root canal sealers in rats. Thirty Wistar rats were divided into three groups according to three time periods (15, 30 and 60 days). Sterilized polyethylene tubes filled with root canal sealers (AH Plus, Epiphany & Grossman), and one empty tube (control) were implanted into four separate dorsal regions in each rat. At the end of each study period, 10 animals were sacrificed, and histologic sections of connective tissue at the open ends of the tubes were prepared. Severity of tissue inflammatory response was assessed. Grossman endodontic sealer had the most severe inflammatory response followed by the AH Plus, Epiphany and control groups. The tissue inflammatory response of the Epiphany and AH Plus sealers was not significantly different. Thus, Epiphany sealer showed acceptable biocompatibility when tested on rat subcutaneous tissue.