Objectives: The purpose of this study was to evaluate the biocompatibility of MTA and the experimentally manufactured portland cement (EMPC). Study design: Twenty one Sprague Dawley (SD) rats were allocated to testing of three groups. Group I and Group II included ProRoot MTA and the EMPC. The materials were mixed with distilled water and placed in polyethylene tubes. The tubes were implanted subcutaneously in the dorsal region of the animals. Group III served as control; the implanted polyethylene tubes remained empty. At 7, 14, and 28 days after the implantation, the animals were sacrificed and the implants were removed with the surrounding tissues. The specimens were prepared for histological examination to evaluate the inflammatory response. Results: No significant difference was found between tissue reactions against the tested materials (p>0.05). Also, control group showed similar results(p>0.05). Conclusions: Results suggest that the EMPC has the potential to be used in clinical conditions in which ProRoot MTA is indicated. MTA and the EMPC show comparable biocompatibility when evaluated in vivo. Although the results are supportive for the EMPC, more studies are required before the safe clinical use of the EMPC.