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This study aimed to evaluate the effect of seven different decontamination methods (water, ZirClean^TM, 37% phosphoric acid, 9.5% hydrofluoric acid, Al₂O₃ sandblasting, low-speed dental stone, and high-speed dental stone) on the fracture resistance, microstructure, and surface roughness of monolithic and multilayered zirconia. The as-received and sandblasted zirconia was used as a control. One-way ANOVA and <i>t</i>-test were performed. As-received monolithic zirconia was stronger (856 ± 94 MPa) than multilayered zirconia (348.4 ± 63 MPa). Only phosphoric acid (865 ± 141 MPa) and low-speed dental stone (959 ± 116 MPa) significantly increased the flexural strength of sandblasted monolithic zirconia (854 ± 99 MPa), but all tested decontamination methods except phosphoric acid (307 ± 57 MPa) and Al₂O₃ (322 ± 69 MPa) significantly increased the flexural strength of sandblasted multilayered zirconia (325 ± 74 MPa). Different decontamination methods did not significantly affect the flexural modulus, but introduced irregularities in the crystal as well as deep surface flaws in both types of zirconia. The surface of sandblasted monolithic zirconia is more resistant to change than multilayered zirconia. Among different decontamination methods, a low-speed dental stone could be beneficial as it significantly increased the surface roughness and fracture resistance of both types of zirconia.