Purpose: The aim of this prospective clinical trial was to evaluate the reliability of three- and four-unit posterior fixed partial dentures (FPDs) with zirconia frameworks after 3 years of clinical function. Materials and Methods: Thirty patients, each needing a posterior FPD to restore one or two missing teeth, were included in the study. Preparation guidelines were: occlusal reduction of 1.5 to 2 mm, axial reduction of 1.5 mm, and circumferential chamfer preparation placed 0.5 mm subgingivally. Frameworks were fabricated using a computer-aided design/computer-assisted manufacture technique. All FPDs were cemented with glass-ionomer cement. At baseline and 12, 24, and 36 months after cementation, survival and success of the zirconia framework and the ceramic veneer were evaluated. To analyze the effect of placement of an all-ceramic restoration on the gingival tissue, Gingival Index, Plaque Index, sulcus bleeding index, and pocket depth at abutment (test) and contralateral analogous teeth (control) were assessed. Data were analyzed by descriptive statistics, the Wilcoxon test, and the McNemar test. Results: Of the 30 initial subjects, 27 patients with 27 zirconia FPDs were examined after a mean testing period of 34.2 months. All FPDs were still in use and unfractured, resulting in a 100% survival rate for the frameworks. One FPD exhibited a major chip after 36 months. The cumulative success rate was 96.3%. No significant differences between the periodontal parameters of the test and control teeth were observed. The Plaque Index revealed significantly higher scores for mesial and distal control teeth at baseline and after 12 and 24 months for distal control teeth. Conclusion: Posterior zirconia-based three- and four-unit FPDs present a reliable treatment modality after medium-term clinical use.