Purpose: The aim of this prospective study was to evaluate the clinical performance of zirconia-based posterior four-unit fixed dental prostheses (FDPs) after 4 years of clinical observation. Materials and Methods: Between 2006 and 2010, 10 patients (5 women, 5 men; mean age: 52.8 years) received 17 posterior four-unit FDPs. Two calibrated examiners evaluated the FDPs independently 1 week (baseline), 6 months, and 1, 2, 3, and 4 years after placement using California Dental Association (CDA) criteria. Periodontal status was assessed on both the abutment and contralateral control teeth using Plaque Index, Gingival Index, probing attachment level, and Margin Index parameters. Statistical analysis was performed using descriptive statistics and the Wilcoxon signed-rank test. Results: Three restorations were lost because of fractures at their distal connectors after a mean clinical service of 25.3 months, and one abutment tooth was extracted because of vertical root fracture 23 months after cementation. Three FDPs presented chipping of a moderate size 1 week before framework fracture, and minor chipping was observed in 2 other FDPs 1 week and 36 months after cementation. After 4 years of clinical service, the cumulative survival rate of the posterior four-unit FDPs was 76.5%. No caries lesions were detected on the abutment teeth. The remaining restorations were judged to be satisfactory according to the CDA criteria. Periodontal parameters did not show significant differences between test and control teeth, but Gingival Index scores demonstrated a slight increase in inflammation in the distal abutments after 4 years (P = .016). Conclusions: The use of zirconia-based posterior four-unit FDPs should be restricted for patients with high esthetic demands, except in patients where at least 4 mm of height is available for connector thickness.