Background: CAD/CAM systems enable the production of fixed partial dentures with small and reproducible internal and marginal gaps. Purpose: The purpose of this study was to evaluate the reproducibility of the marginal and internal adaptations of four-unit fixed partial denture frameworks produced using four CAD/CAM systems. Materials and Methods: Prepared dies of a master model that simulated the loss of the first left molar were measured. Fifteen frameworks were manufactured using four CAD/CAM systems (A–D). The internal fit was determined by the replica technique, and the marginal gap was determined by microscopy. ANOVA was carried out to detect significant differences, and the Bonferroni adjustment was performed. The global level of significance was set at 5%. Results: The mean gap size ranged from 84 to 132 µm (SD 43–71 µm). The CAD/CAM systems showed significant variance (p p < 0.001). Conclusions: The CAD/CAM systems showed significantly different gap sizes, particularly between premolars and molars and among the marginal, axial and occlusal regions. All of the systems are suitable for clinical application.