This study aimed to evaluate the impact of digital vs traditional impression techniques on peri-implant vertical bone resorption in the creation of mandibular overdenture bases supported by four implants using CAD/CAM technology. Twenty edentulous patients were placed in four mandibular implants and randomly divided into groups: (A) the control group (CIG) (n = 10); patients obtained CAD/CAM denture base using conventional impression technique and group (B) the study (DIG) group (n = 10); patients obtained CAD/CAM denture base using digital impression technique. Peri-implant vertical bone height was measured immediately (T0), 6 (T6), and 12 (T12) months after insertion. Peri-implant vertical bone loss (VBL) was calculated first 6 months (T1), the second 6 months (T2), and 1 year (T3) after insertion. For both groups, the survival rates of inserted implants were 100%. The amount of VBL in the first year in both groups was within normal ranges. In both groups, VBL significantly decreased over time. The control group recorded significantly higher VBL than (DIG) group at T2 (p = 0.006) and at T3 (p = 0.005). Digital intraoral scanning technique may be considered a more beneficial registration method than traditional impression technique for the construction of CAD/CAM 4-implant-assisted overdenture base regarding the preservation of vertical bone levels. Both digital intraoral scanners and conventional impression techniques can be used for the construction of CAD/CAM-implant-assisted overdenture bases regarding the preservation of peri-implant vertical bone resorption. How to cite this article: Seifeldeen AR, Aboelez MA, Gebreel AA, et al. Comparison of Direct Intraoral Scan and Traditional Impression for CAD/CAM Mandibular Overdenture Base: RCT on Peri-implant Marginal Bone Changes. J Contemp Dent Pract 2024;25(6):527-534.