Purpose: The aim of this retrospective cohort study was to evaluate the clinical performance of tooth-supported zirconia-based fixed dental prostheses (FDPs) made by 15 members of the Italian Academy of Prosthetic Dentistry over a time period of up to 5 years. Materials and Methods: Ninety-eight patients were treated with a total of 137 zirconia-based FDPs in anterior and posterior regions using primarily chamfer or knife-edge tooth preparations. The cohort group with parafunctional habits was compared with patients without parafunctional habits according to the esthetic, functional, and biologic United States Public Health Service criteria modified by the FDI World Dental Federation. Results: The estimated cumulative survival of all restorations was 94.70% ± 1.25% standard error (SE), whereas the estimated cumulative success decreased to 89.78% ± 2.58 SE. Mechanical failures, including three zirconia framework fractures, two hairline cracks, nine chippings, and one delamination of the ceramic veneering, were recorded during the 1-to 5-year observation period. An odds ratio of 2.02 (95% confidence interval: 0.67 to 6.12) showed a moderate association between parafunction and failure. Conclusions: Zirconia-based tooth-supported FDPs showed promising clinical results over a period of up to 5 years. Technical complications were more commonly detected in patients with parafunctional habits.