Purpose: The aim of this study was to compare the survival rates and biologic and technical complications of three-unit metal-ceramic posterior fixed dental prostheses (FDPs) with those obtained with zirconia frameworks. Materials and Methods: Thirty-seven patients in need of 40 three-unit posterior FDPs were included in this study. The FDPs were randomly assigned to 20 zirconia and 20 metal-ceramic restorations. Abutment preparation guidelines consisted of a 1-mm-wide circumferential chamfer, axial reduction of 1 mm, and occlusal reduction of 1.5 to 2 mm. At baseline and 1, 2, 3, and 4 years after cementation, success of both types of restorations was evaluated. The restorations were assessed using the California Dental Association's assessment system. Periodontal parameters were assessed by determining the Plaque Index (PI), Gingival Index (GI), Marginal Index (MI), and pocket depth of the abutment and control teeth. Statistical analysis was performed by applying Wilcoxon rank sum and Wilcoxon signed-rank tests. Results: Patients were examined after a mean observation period of 50 ± 2.4 months. The survival rates for metal-ceramic and zirconia restorations were 100% and 95%, respectively. One biologic complication in a zirconia FDP was observed at the 3-year follow-up. No fractures of the zirconia or metal frameworks were observed. Restorations from both groups were assessed as satisfactory. Minor chipping of the veneering ceramic was observed in 2 zirconia FDPs after 4 years. No significant differences were observed between abutment and contralateral teeth for either type of restoration or within the groups with regard to PI, GI, and pocket depth. Conclusion: Zirconia-based FDPs demonstrated a similar survival rate to metal-ceramic FDPs after medium-term clinical use.