Objective: To evaluate the effect of the endodontic sealer Epiphany on rat peritoneal macrophages viability. Materials and methods: Peritoneal macrophages were obtained from Wistar rats and resuspended in RPMI- 1640 medium. Undiluted (crude extract) and diluted extracts to 10%, 1%, 0.1%, 0.01%, 0.001% and 0.0001% of Epiphany, AH 26 and AH Plus sealers on RPMI-1640 medium were tested for cytotoxicity to rat peritoneal macrophages using the trypan blue dye exclusion assay. Data were analyzed statistically by the Kruskal-Wallis and Mann-Whitney tests at 5% significance level. Results: Crude extract of Epiphany killed 51% of cells, but was less cytotoxic that crude extracts of AH Plus and AH 26, which killed 81% and 86% of cells, respectively. Ten-fold dilutions of Epiphany, AH Plus and AH 26 killed 44%, 56%, 62% of macrophages, respectively. A hundred dilution of Epiphany only killed 7% of macrophages, but the same dilution of AH Plus and AH 26 killed 10% and 31% of macrophages, respectively. Lower dilutions of sealer extracts caused minimal cell death as compared to the control groups (p>0.05). Conclusions: The methacrylate-based endodontic sealer Epiphany showed lower cytotoxicity on macrophages than resin-based sealers AH Plus and AH 26. Dilution of elutes of the three materials by tenfold markedly reduced their effects