Non-surgical root canal treatment is a probable treatment plane in many endodontic cases, although surgery may be selected for teeth with insistent periapical pathogenesis which is not reactive to non_surgical means or once non-surgical retreatment is unsuccessful Objective This study was conducted to evaluate the biocompatibility of two bioactive materials, Cention N (CN) and ACTIVA bioactive, then compare the result with that of Mineral Trioxide Aggregate (MTA) as a retrograde filling materials. Materials and Methods Sixty Albino male rats were used in the study, four polyethylene tubes were subcutaneously implanted into the rats, an empty one was used as a control group, and the other three tubes were filled with ACTIVA, Cention N and MTA-HP. Rats were then divided into three groups (n = 20 rats) following the sacrification time into three intervals: one, two and three weeks, then, the tissue specimens were analyzed histopathologically. The collected data were subjected to statistical analysis. Results ANOVA test showed that the lowest inflammatory reaction was recorded for ACTIVA while a high degree of chronic inflammation was recorded for MTA group, with highly significant differences, P< 0.001. ACTIVA bioactive material exhibited observable decline of inflammation and fibrosis in a comparison to the control. Conclusions The two bioactive materials showed a higher biocompatibility comparable to MTA. ACTIVA showed the highest degree of biocompatibility related to the decreased intensity of inflammation, with well-formed fibrous connective tissue conversion and improved healing patterns.