Objective: The purpose of the present study was to evaluate the inflammatory response caused by three calcium silicate based cements in rat’s subcutaneous tissue. Materials and methods: Fifteen Wistar rats were divided into three groups of 1, 4, and 8 experimental weeks. Sterile silicone tubes were filled with Micro-Mega Mineral Trioxide Aggregate (MM-MTA), Biodentine (BD) and EndoSequence Root Repair Material (ESRRM) putty and implanted subcutaneously. Empty tubes were implanted as negative control. After the experimental periods, all animals were sacrificed and the specimens stained histologically with hematoxylin-eosin (H&E), Masson’s trichrome and Toluidine blue to assess the type of inflammation, intensity and extent of inflammatory cells, foreign body reaction, fibrous capsule thickness, coagulated necrosis, capillary reaction and vascular congestion, amount and the distribution of mature collagen and mast cell population. Statistical analysis was performed by the Kruskal-Wallis and Mann-Whitney U tests. The level of significance was 5% (P<0.05). Results: MM-MTA provoked severe inflammation after 1 week, which was significantly different from ESRRM putty and control (P<0.05); BD produced less biological reaction than MM-MTA and more than ESRRM and control during the initial periods. While both MM-MTA and BD had reduced inflammatory reaction with time. ESRRM showed tissue-tolerance features almost comparable to control during all experimental periods. Conclusion: ESRRM putty was significantly more biocompatible than MM MTA and BD in the 1st week of the experiment. However, there was no significant difference between the materials at the end of the 8th weeks. ESRRM putty, BD, and MM MTA can be considered suitable calcium silicate materials.