Satisfactory biological behavior is a necessary requirement for clinical application of endodontic materials. In this study, the connective tissue responses to silicone (GuttaFlow 2), epoxy resin (AH Plus) and zinc oxide and eugenol (Endofill) based sealers were compared. Twelve Wistar rats had polyethylene tubes (four per animal) containing one of the tested sealers and empty tubes (negative control) implanted in their subcutaneous tissue. The tubes were randomly placed 2 cm from the spine and at least 2 cm apart from one another. Tissue samples with implants were processed for histological analysis after 7 or 60 days (n=6 animals per period). Inflammatory cells, fibrous condensation and abscess were scored according to their intensity. Friedman, followed by Dunn's post hoc, was used to compare sealers. Differences between the two experimental periods were verified using Mann-Witney U test (p<0.05). At 7 days, most of the histological parameters showed no significant differences amongst groups. Endofill group scored higher than the others for giant cells (o<0.05) and promoted a greater number of samples presenting abscess formation. GuttaFlow 2 tended to show a less intense inflammatory infiltrate compared to the other materials. At 60 days, there were no significant differences between groups in most of the histological parameters evaluated. However, it was observed that Endofill scored higher for macrophages (p<0.05) compared to the control group, and GuttaFlow 2 tended to present lower scores than the others for neutrophils and abscess. GuttaFlow 2 showed proper biological behavior and should be considered adequate for clinical practice.