This study was designed to test the impact of either a strong (MTAD) or a soft (1-hydroxyethylidene-1, 1-bisphosphonate [HEPB]) chelating solution on the bond strength of Resilon/Epiphany root fillings. Both 17% EDTA and the omission of a chelator in the irrigation protocol were used as reference treatments. Forty extracted human upper lateral incisors were prepared using different irrigation protocols (n = 10): G1: NaOCl, G2: NaOCl + 17% EDTA, G3: NaOCl + BioPure MTAD (Dentsply/Tulsa, Tulsa, OK), and G4: NaOCl + 18% HEPB. The teeth were obturated and then prepared for micropush-out assessment using root slices of 1 mm thickness. Loading was performed on a universal testing machine at a speed of 0.5 mm/min. One-way analysis of variance and Tukey multiple comparisons were used to compare the results among the experimental groups. EDTA- and MTAD-treated samples revealed intermediate bond strength (0.3-3.6 MPa). The lowest bond strengths were achieved in NaOCl-treated samples (0.3-1.2 MPa, p < 0.05). The highest bond strength was reached in the HEBP-treated samples (3.1-6.1 MPa, p < 0.05). Under the present in vitro conditions, the soft chelating irrigation protocol (18% HEBP) optimized the bonding quality of Resilon/Epiphany (Resilon Research LLC, Madison, CT) root fillings.