Purpose: The aim of this randomized controlled clinical trial was to compare the outcomes of zirconia crowns and fixed partial dentures (FPDs) supported by teeth or implants. Materials and Methods: Patients were recruited based on inclusion/exclusion criteria, and 59 eligible subjects were assigned randomly to treatment by one of four zirconia systems (Cercon, ZirkonZahn, Lava, and Katana). One hundred seven single-tooth and 160 three- to six-unit FPDs were fabricated on teeth and implants and cemented using composite resin cement. Californian Dental Association (CDA) quality evaluation, Plaque Index, and Gingival Index scores were recorded, and radiographic assessment of the restorations was performed using periapical and panoramic radiographs at baseline and annually up to 4 years. Results: Five failures (1.9%) were recorded. The 4-year Kaplan-Meier survival probabilities of FPDs were higher than those of single-tooth restorations (P = .046). The highest survival probability for crowns was observed for Katana and the lowest for Cercon (P < .05). For FPDs, the survival probabilities of Lava restorations were similar to those of Cercon but lower than those of ZirkonZahn and Katana (P < .05). The 4-year survival probabilities of implant- and tooth-supported crowns were comparable (P = .182), Regarding CDA ratings, the slight marginal discrepancy scores for the Cercon restorations were higher than for the other systems at 1 year (P < .05). In FPDs, 94.5% of Katana FPDs had slight or gross color mismatch scores, and the difference between color and surface ratings among zirconia systems was significant (P < .05). FPDs had better periodontal scores than crowns over the 4-year observation period (P < .05). Conclusion: The 4-year interim results of this study suggest that zirconia systems used to fabricate FPDs have predictably high survival rates on teeth and implants and may exhibit differences, particularly in terms of mechanical failures, marginal adaptation, and color matching. Int J Prosthodont 2012;25:221-231.