Background: The aim of the present study was to evaluate the accuracy of prosthetically guided maxillofacial surgery in reconstructing the mandible with a free vascularized flap using custom-made bone plates and a surgical guide to cut the mandible and fibula. Methods: The surgical protocol was applied in a study group of seven consecutive mandibular-reconstructed patients who were compared with a control group treated using the standard preplating technique on stereolithographic models (indirect computer-aided design/computer-aided manufacturing method). The precision of both surgical techniques (prosthetically guided maxillofacial surgery and indirect computer-aided design/computer-aided manufacturing procedure) was evaluated by comparing preoperative and postoperative computed tomographic data and assessment of specific landmarks. Results: With regard to midline deviation, no significant difference was documented between the test and control groups. With regard to mandibular angle shift, only one left angle shift on the lateral plane showed a statistically significant difference between the groups. With regard to angular deviation of the body axis, the data showed a significant difference in the arch deviation. All patients in the control group registered greater than 8 degrees of deviation, determining a facial contracture of the external profile at the lower margin of the mandible. With regard to condylar position, the postoperative condylar position was better in the test group than in the control group, although no significant difference was detected. Conclusions: The new protocol for mandibular reconstruction using computer-aided design/computer-aided manufacturing prosthetically guided maxillofacial surgery to construct custom-made guides and plates may represent a viable method of reproducing the patient’s anatomical contour, giving the surgeon better procedural control and reducing procedure time. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.