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The aim of this study was to evaluate the biocompatibility and immunoinflammatory response of the Sealepox and Sealepox-RP, based on interleukin (IL)-6, tumor necrosis factor (TNF)-α, and CD5 immunolabelling. The ProRoot MTA (PRMTA) was used for comparison. Polyethylene tubes (1.0-mm internal, 1.6-mm external diameter, and 10.0-mm length; ISO 10993) with or without (control) materials were randomly implanted in the dorsum of 35 rats (4 per rat). After 7, 15, 30, 60, and 90 days (n = 7), the tubes were removed for histological and immunohistochemical analysis. The Kruskal–Wallis and Dunn's test for non-parametric data and, ANOVA and Tukey test for parametric data were used (P < 0.05). Hematoxylin and eosin staining revealed that the concentration of inflammatory cells decreased over time with no differences between groups in all periods (P > 0.05). Regarding IL-6 immunostaining, there was no difference at 7 days (P > 0.05); all groups decreased over time, being faster for the PRMTA group and also, with no differences between groups in the last period (P > 0.05). For TNF-α, at 7 days there was no difference between groups (P > 0.05); there was an increase at 15 days for PRMTA and, at 30 and 60 days, for PRMTA and Sealepox compared to the control (P < 0.05). At 90 days, Sealepox RP showed the lowest immunostaining being similar to the control (P > 0.05). Regarding CD5 cells, at 7 days, there was high immunostaining for PRMTA compared to the control (P < 0.05); and significant reduction over time with difference for all groups at 30 and 60 days. (P < 0.05); Sealepox was similar to the control in all periods (P > 0.05). Sealepox RP showed the highest immunostaining at 15 days, being different from the control and PRMTA (P < 0.05); in the other periods it was similar to the control (P > 0.05). It can be concluded that Sealepox and Sealepox-RP were biocompatible and demonstrated similar immunoinflammatory response regarding IL-6, TNF-α, and CD5 compared to PRMTA. [ABSTRACT FROM AUTHOR]