Purpose: The aim of this prospective clinical cohort study was to determine the success rate of 3- to 5-unit zirconia frameworks for posterior fixed partial dentures (FPDs) after 5 years of clinical observation. Materials and Methods: Forty-five patients who needed at least 1 FPD to replace 1 to 3 posterior teeth were included in the study. Fifty-seven 3- to 5-unit FPDs with zirconia frameworks were cemented with 1 of 2 resin cements (Variolink or Panavia TC). The following parameters were evaluated at baseline, after 6 months, and 1 to 5 years after cementation at test (abutments) and control (contralateral) teeth: probing pocket depth, probing attachment level, Plaque Index, bleeding on probing, and tooth vitality. Intraoral radiographs of the FPDs were taken. Statistical analysis was performed using descriptive statistics, Kaplan-Meier survival analysis, and the McNemar test. Results: Twenty-seven patients with 33 zirconia FPDs were examined after a mean observation period of 53.4 ± 13 months. Eleven patients with 17 FPDs were lost to follow-up. After the 3-year recall visit, 7 FPDs in 7 patients were replaced because they were not clinically acceptable due to biologic or technical complications. After 5 years of clinical observation, 12 FPDs in 12 patients had to be replaced. One 5-unit FPD fractured as a result of trauma after 38 months. The success rate of the zirconia frameworks was 97.8%; however, the survival rate was 73.9% due to other complications. Secondary caries was found in 21.7% of the FPDs, and chipping of the veneering ceramic in 15.2%. There were no significant differences between the periodontal parameters of the test and control teeth. Conclusions: Zirconia offers sufficient stability as a framework material for 3- and 4-unit posterior FPDs. The fit of the frameworks and veneering ceramics, however, should be improved