Aim To record the cytotoxicity of Resilon and Epiphany (Pentron clinical technologies, Wallingford, CT,USA) using a root model.Methodology Thirty teeth with single roots were sectioned at the enamel-cementum junction, the root canals prepared and each root then sterilized before filling with the lateral condensation technique using one of three filling materials (n ¼ 10 per group): Resilon and Epiphany, Sealite (Septodont, Pierre Rolland, Merignac, France) and gutta-percha, Roekoseal Automix (Coltène/Whaledent, Langenau, Germany) and gutta-percha. The roots were stored at 37°C in an incubator to allow for setting of the root filling materials. The apices of the roots were dipped in 1 mL of MEM culture medium for 1, 2, 7 and 30 days renewing the medium every day. After 24 h contact between the medium and the filled roots, the medium was used to measure the cytotoxicity on mouse fibroblasts L 929 with the MTT assay that recorded the mitochondrial activity of the target cells. An additional test according to ISO 10993-5 standards was undertaken to compare Resilon and Epiphany. Results The root model showed no statistically significant differences between the sealers at 7 and 30 days (NS). Epiphany and Resilon were the most cytotoxic materials at 1 and 2 days (P < 0.001). Unlike Epiphany, Resilon was not cytotoxic when tested according to ISO 10993-5 standards. Conclusions The cytotoxicity of Resilon + Epiphany, due mainly to Epiphany, decreased after 2 days to reach a level comparable with commonly used root canal sealers.