Considering that endodontic sealers release some components which may promote delay in the repair process, our purpose was to evaluate the tissue reaction promoted by MTA Plus and MTA Fillapex in comparison with AH Plus (standard control) and Endofill, which has a long clinical track record. One hundred rats were distributed into five groups: MTA Plus (Avalon Biom Inc., Bradenton, FL, USA), MTA Fillapex (Angelus, Londrina, PR, Brazil), AH Plus (Dentsply DeTrey GmbH, Konstanz, Germany), Endofill (Dentsply, Petrópolis, RJ, Brazil) and CG (control group, empty polyethylene tubes). The polyethylene tubes filled with sealers or empty (CG) were implanted into subcutaneous. After 7, 15, 30 and 60 days, the tubes surrounded by capsules were paraffin-embedded. In HE-stained sections, the volume density of inflammatory cells (VvIC) was estimated in the capsules. The number of interleukin-6-immunolabelled cells (IL-6), a pro-inflammatory cytokine, was also computed in the capsules. The birefringent collagen content was quantified in picrosirius-stained sections. Data were analysed by ANOVA and Tukey tests (p ≤ 0.05). At 7 days, the capsules showed moderate inflammatory reaction. In all groups, VvIC and IL-6-immunostained cells reduced significantly from 7 to 60 days. At 60 days, IL-6 immunoexpression was reduced significantly in MTA Plus and MTA Fillapex in comparison with AH Plus; no difference was found in the VvIC among MTA Plus, MTA Fillapex, AH Plus and CG whereas Endofill exhibited the highest VvIC. The reduction in VvIC was parallel to an increase in the collagen in all the groups, except Endofill. MTA Plus, MTA Fillapex and AH Plus induce a response that culminates in the regression of inflammation and formation of a fibrous capsule over time. The lower IL-6 immunoexpression in the capsules of MTA Plus and MTA Fillapex than AH Plus suggests that the immune response is suppressed more rapidly in the MTA-based sealers.