In this prospective clinical trial we observed the 2-year clinical performance of posterior tooth-supported multi-unit fixed dental prostheses (FDP) fabricated from zirconia with monolithic occlusal surfaces. Fifty multi-unit FDPs were inserted in 50 patients. After two years of clinical service, 43 restorations were reexamined as one patient had died and six patients were not available for recall. Two biological (root canal treatment: 12 and 14 months) and one technical (debonding: 12 months) complications occurred. According to the Kaplan–Meier analysis, the success rate was 93.7%, and the survival rate was 100%. The six patients who were not available for regular 2-year follow-up were examined after the official 2-year recall interval, and none of the FDPs presented complications or failures. Within the limitations of the current study, the use of multi-unit FDPs with monolithic occlusal surfaces fabricated from zirconia can be recommended for short-term use in the posterior area.