Objective: The aim of this multicenter randomized controlled clinical trial was to test posterior zirconia-ceramic fixed dental prostheses (FDPs) veneered with a computer-aided design/computer- assisted manufacture (CAD/CAM) lithium disilicate veneering ceramic (CAD-on) and manually layered zirconia veneering ceramic with respect to survival of the FDPs, and technical and biologic outcomes. Method and Materials: Sixty patients in need of one posterior three-unit FDP were included. The zirconia frameworks were produced with a CAD/CAM system (Cerec inLab 3D/Cerec inEOS inLab). Thirty FDPs were veneered with a CAD/CAM lithium disilicate veneering ceramic (Cad-on) (test) and 30 were veneered with a layered zirconia veneering ceramic (control). For the clinical evaluation at baseline, 6, and 12 months, the United States Public Health Service (USPHS) criteria were used. The biologic outcome was judged by comparing the plaque control record (PCR), bleeding on probing (BOP), and probing pocket depth (PPD). Data were statistically analyzed. Results: Fifty-six patients were examined at a mean follow-up of 13.9 months. At the 1-year follow-up the survival rate was 100% in the test and in the control group. No significant differences of the technical outcomes occurred. Major chipping occurred in the control group (n = 3) and predominantly minor chipping in the test group (minor n = 2, major n = 1). No biologic problems or differences were found. Conclusions: Both types of zirconia-ceramic FDPs exhibited very good clinical outcomes without differences between groups. Chipping occurred in both types of FDPs at small amounts, yet the extension of the chippings differed. The test FDPs predominantly exhibited minor chipping, the control FDPs major chipping. Keywords: CAD/CAM, CAD-on, fixed dental prosthesis, lithium disilicate, zirconia