Purpose: To assess the influence of a screw access hole (SAH) and mechanical cycling on the fracture load of implant-supported crowns (ISCs) manufactured with screw-retained (s) or cement-retained (c) abutments with either metal (M) or zirconia (Z) infrastructure. Materials and Methods: Six groups of restorations were made based on type of infrastructure (M or Z), fixation (s or c), and whether they underwent aging (a) with mechanical cycling: Zc, Zs, Zsa, Mc, Ms, and Msa. All ISCs were porcelain veneered and tested for compression to failure in distilled water (37°C) using a universal testing machine. ISCs from groups Zsa and Msa were mechanically cycled (106 cycles; 2 Hz, 100 N) in distilled water before compressive testing. Fractographic principles were followed to assess the fracture surfaces. The fracture load data were statistically analyzed using one-way analysis of variance and Tukey test (α = .05). The relationships between experimental group and failure mode were analyzed using chi-square test (α = .05). Results: Regardless of the infrastructure material, cement-retained ISCs (Zc and Mc) showed higher fracture load values than screw-retained ISCs (Zs, Zsa, Ms, and Msa) (P .001), which were statistically similar to each other (P > .05). Aging had no effect on the fracture load of ISCs. There was a significant relationship between failure mode and experimental group (P .001). Catastrophic fractures were found only in Zc and Zs. All metal-based ISCs failed from chipping reaching the metal infrastructure. Conclusion: Cement-retained ISCs showed higher fracture resistance than screw-retained prostheses. No catastrophic failures were found for metal-based ISCs. Aging did not affect the fracture load, but did affect the failure mode of ISCs.