Abstract: In this in vivo study, the skin reactivity of rabbits to Mineral Trioxide Aggregate (MTA) and Calcium Enriched Mixture (CEM) was compared. Sixteen albino rabbits were used. The dorsal skin in three areas (2x2 cm) of the rabbits was shaved 24 h prior to the test. The areas were randomly covered with freshly mixed biomaterials [MTA (n = 16), CEM (n = 16) and normal saline (control; n = 16)], sterile gauze and bandages were placed for 4 h and the biomaterials were washed. The surface areas of the reactive skin sections were examined by naked eye and measured in 1, 24, 48 and 72 h using the Cavalier technique. The animals were then sacrificed and histological sections were prepared for blind examination. Results of macroscopic examination revealed a significant difference (p = 0.003) between the average erythematous surface areas induced by MTA (1.61±0.32) and CEM (0.5±0.16). Results of histological examination showed that the highest inflammation was observed in MTA, followed by CEM and control groups. Comparison of the difference in inflammatory cell count between each group revealed statistically significant differences in all cases (p<0.001). The results demonstrated that the biocompatibility of CEM cement is higher than MTA; CEM can be considered as a suitable endodontic biomaterial.