ObjectiveThis double-blind, randomized, crossover, clinical trial aimed to evaluate and compare the differences between milled and 3D-printed complete removable dental prostheses (CRDPs). MethodsFifteen edentulous patients (men: n = 10, women: n = 5; age: 66.7 ± 8.0 years) rehabilitated with conventional CRDPs were recruited for this trial. Participants were randomized to first receiving either the milled or 3D-printed CAD-CAM manufactured CRDPs and then after 6-weeks cross over to the other set. Both, clinicians and participants were blinded to the group allocation. Outcomes included patient's denture satisfaction (PDS), oral-health related quality of life (OHIP-EDENT), willingness-to-pay analysis, final choice (FC) of CRDPs, clinician's denture quality evaluation (CDQE), chewing efficiency (CE), maximum-voluntary-bite-force (MBF), and prosthodontic maintenance needs. The outcomes were measured at baseline (with old CRDPs), at 1 and 6 weeks after new CRDP insertion; following crossover with the second set of CRDPs, an identical protocol was followed. Generalized linear regression for repeated measures was used for statistical analysis with α=0.05. ResultsAll participants completed the trial. 3D-printed CRDPs required more maintenance visits, adjustment time (p = 0.0003), and adjustment costs (p = 0.021). Patients were willing-to-pay an average of 606.67 Swiss Francs more than the actual cost for the milled CRDPs. There were no differences in the PDS, OHIP, FC, CDQE, CE, and MBF between the two CRDPs groups. ConclusionsThe findings of this double-blind randomized crossover clinical trial confirm that both milled and 3D-printed CRDPs are valid treatment modalities for edentulous patients, with the latter performing inferiorly with regard to the time and costs involved with the prosthodontic aftercare, as well as the patients’ willingness-to-pay. Clinical relevanceThe findings of this trial provide evidence to help the clinician in choosing the appropriate CAD-CAM manufacturing process for fabricating the CRDPs.