The aim of this study was to compare the clinical properties of tooth-colored computer-aided design/computer-aided manufacturing (CAD/CAM) materials for the fabrication of a 3-unit fixed dental prostheses (FDPs) in the same clinical scenario. A 53-year-old female patient was supplied with a 3-unit FDP to replace a second premolar in the upper jaw. Restorations were fabricated from 3 mol%, 4 mol%, and 5 mol% yttrium oxide zirconia, zirconia with translucency gradient, indirect composite resin, polyetheretherketone (PEEK), and polyetherketoneketone (PEKK). Milling time, weight, and radiopacity were investigated. Esthetics were examined following the US Public Health Service criteria (USPHS). The milling time for zirconia was twice as high as for the indirect composite resin, PEEK, or PEKK. The latter materials had a weight of 2 g each, while zirconia restorations yielded 5 g. Zirconia presented intense radiopacity. PEEK and PEKK required veneering and an opaquer was applied to the PEKK framework. All FDPs showed acceptable esthetics. PEEK and PEKK restorations were featured by a grayish shimmering. A variety of CAD/CAM materials are available to fabricate 3-unit FDPs with esthetically acceptable results. In the esthetic zone, PEEK and PEKK require veneering and an opaquer might be applied. Milling time, weight, and radiopacity were relatively high for zirconia FDPs.