To evaluate the effect of GuttaFlow bioseal (GFB) and MTA Fillapex (MTAF) in comparison with Endofill (EF) in the subcutaneous tissue. Polyethylene tubes with GFB, MTAF, EF or empty tubes (control group; CG) were implanted into subcutaneous of rats. After 7, 15, 30 and 60 days, the capsule thickness, inflammatory reaction, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), caspase-3, TUNEL-positive cells, von Kossa and ultrastructural features were evaluated. The data were statistically analyzed (p ≤ 0.05). At all periods, the number of IL-6-and VEGF-immunolabelled cells, and capsule thickness were lower in GFB than MTAF, which was lower than EF (p < 0.0001). At 60 days, the number of inflammatory cells was similar in GFB and MTAF (p = 0.58). Significant differences in the number of TUNEL-and caspase-3-positive cells were not observed among GFB, MTAF and CG whereas the highest values were found in EF specimens. The EF specimens exhibited several cells with condensed chromatin, typical of apoptosis. von Kossa-positive and birefringent structures were only observed in GFB and MTAF, suggesting the presence of calcite crystals. Taken together, these results show that cellular and structural damage induced by GFB and MTAF sealers were recovery over time. Moreover, these sealers express bioactive potential in subcutaneous tissue.The clinical use indication of root canal sealers depends on their physicochemical and biological properties. Thus, the biological properties of endodontic sealers and degree of cytotoxicity on different cells, including fibroblasts, osteoblasts and cementoblasts have been widely investigated 1 . However, in vitro studies have the disadvantage of reflecting the response to a specific cell type and, therefore, do not reflect the host response, which is under influence of several cytokines and growth factors 2 . The implant into subcutaneous connective tissue is widely used to evaluate the biocompatibility and the complex cascade of cellular and molecular events induced by dental materials 2-5 .Studies have suggested that silicone-based endodontic sealers exhibit proper physicochemical and biological properties 6,7 . A novel formulation of silicone-based sealer, the GuttaFlow bioseal (GFB; Coltene Whaledent, GmBH + Co KG, Langenau, Switzerland) is a mixture of gutta-percha powder and polydimethylsiloxane with silver nanoparticles added as a preservative; silica, calcium oxide and phosphorous oxide particles were also combined to this mixture to provide bioactivity and stimulate the tissue repair. The GFB has low solubility and porosity, alkalinizing activity and slight calcium release 8,9 . An in vitro study using human periodontal ligament cells has demonstrated that GFB displays better cytocompatibility than AH Plus 10 , which is considered as a gold standard in the clinical endodontic.Considering the suitable biocompatibility of MTA (Mineral Trioxide Aggregate, Angelus, Londrina, PR, Brazil), the manufactures have added tricalcium silicate to resin-based sealers in an attempt to ...