Objectives: This review compared the differences between Computer-aided design- computer-aided manufacturing (CAD-CAM) and conventionally manufactured removable complete dentures (CDs). Data: Seventy-three studies reporting on CAD-CAM (milled/3D-printed) CDs were included in this review. Last search was performed on 15/03/2021. Sources: Two investigators searched electronic databases [PubMed (MEDLINE), Embase, CENTRAL], online search engines (Google) and research portals. Hand searches were performed to identify literature not available online. Study selection: Studies on CAD-CAM CDs were included if they reported on trueness, biocompatibility, mechanical-, surface-, chemical-, color-, and microbiological- properties, time-cost analysis, and clinical outcomes. Inter-investigator reliability was assessed using kappa. Meta-analysis was performed on the extracted parameters. Results: The kappa ranged between 0.897–1.000. Meta-analyses revealed that 3D- printed CDs were more true than conventional (p=0.039). Milled had a higher flexural- strength than conventional and 3D-printed (p<0.0001). Milled had a higher flexural- modulus than 3D-printed CDs (p<0.0001). Milled had a higher yield-strength than injection-molded (p=0.004), and 3D-printed (p=0.001). Milled was better in toughness (p<0.0001) and surface roughness (p<0.0001) than others. Rapidly-prototyped CDs had a low color-stability compared to others CD groups (p=0.029). CAD-CAM CDs were better than conventional in retention (p=0.015). Conventional CDs had a higher strain at yield point than milled (p<0.0001), and were better in esthetics than 3D- printed (p<0.0001). Fabrication of CAD-CAM CDs required lesser chairside time (p=0.037) and overall costs (p<0.0001) than conventional CDs. Conclusions: This systematic review concludes that CAD-CAM CDs offer a number of improved mechanical/surface properties and are not inferior when compared to conventional CDs. Clinical significance : CAD-CAM CDs should be considered for completely edentulous patients whenever possible, since this technique offers numerous advantages including better retention, mechanical- and surface properties but, most importantly, preserves a digital record. This can be a great advantage for elders with limited access for dental care.