This prospective study evaluated the clinical outcome of three-unit posterior fixed dental prostheses (FDPs) made of In-Ceram Zirconia. All 65 FDPs were inserted at the Department of Prosthodontics, School of Dentistry, Kiel, Germany, and cemented with glass-ionomer cement. Follow-ups were performed annually. During a mean observation time of 54.4 months, two FDPs failed (one technical and one biologic failure). Two FDPs debonded and the veneering ceramic fractured in four cases. Three abutment teeth needed endodontic treatment and two additional abutment teeth exhibited secondary caries. Results suggest that posterior three-unit all-ceramic FDPs made from In-Ceram Zirconia may be a viable prosthetic treatment option with an outcome comparable to metal-ceramic FDPs.