The purpose of this study was to assess the apical sealing ability of the new resin-based Epiphany-Resilon root canal filling system, and to compare this with the sealing abilities of different pairings of AH plus, gutta-percha, Epiphany, and Resilon. Seventy extracted human single-rooted teeth were used. All teeth were instrumented using a set of ProTaper rotary instruments. The canal spaces were filled with different combinations of core and sealer using lateral condensation, as follows: group 1, AH Plus + gutta-percha; group 2, AH Plus + Resilon; group 3, Epiphany + Resilon; group 4, Epiphany + gutta-percha. Apical leakage quantity was measured with the computerized fluid filtration meter. Statistical analysis indicated that Epiphany gutta-percha combination had the least amount of microleakage than all the other groups; AH Plus gutta-percha combination proved to have second least amount of microleakage among the groups. AH Plus-Resilon combination demonstrated the greatest amount of microleakage. There were a significant difference between Epiphany gutta-percha and AH Plus-Resilon combinations (p < 0.05). It was found that there were no significant differences between Epiphany-Resilon combination and all the other groups (p > 0.05).