Purpose: The purpose of this study was to evaluate the marginal adaptation of fixed dental prosthesis frameworks fabricated by computer-aided design/computer-assisted manufacture (CAD/CAM) with three different systems of data acquisition. Materials and Methods: A total of 50 specimens were fabricated as follows: using the conventional method (Ni-Cr) (n = 10); iTero/industrial milling (Group 1, n = 10); Cerec Bluecam/industrial milling (Group 2, n = 10); 3S/industrial milling (Group 3, n = 10); and Cerec BlueCam/Sirona milling (Group 4, n = 10). The specimens were numbered and randomized, and the vertical marginal discrepancy was analyzed. Results: Intraobserver analysis indicated no statistically significant difference (paired t test, P = .822) between periods before and after analysis. The conventional method (321 μm) showed greater discrepancy when compared with the CAD/CAM system (89 μm) (P .001). The intraoral system showed a lower rate of marginal discrepancy when compared with the extraoral system (3S) (P .001). The closed system presented a higher marginal discrepancy (114 μm) than the open intraoral system (iTero) at P .001. In addition, the intraoral system when open showed statistically significant differences in mean marginal discrepancy values compared with the same system in closed condition (P > .05). Conclusion: The CAD/CAM systems showed less marginal discrepancy than the conventional method for the fabrication of the frameworks.