Objectives: The primary objective was to assess the impact of two denture fabrication techniques, conventional and CAD/CAM, on oral health-related quality of life (OHRQoL) and patient satisfaction in complete denture wearers. The secondary objective was to compare the level of microorganisms present on complete dentures from the two fabrication techniques. Methods: Twenty-eight completely edentulous subjects (16 men and 21 women, age range from 49 to 87 years old.), who had been edentulous for at least 6 months, were wearing ill-fitting complete dentures, or unsatisfied with their existing complete dentures were recruited. Subjects were randomized to conventional and computer-aided design/ computer-aided manufacturing (CAD/CAM) treatment groups. Subjects in both groups were given the OHIP-EDENT (Oral Health Impact Profile for Edentulous Patients) and patient satisfaction questionnaires to record the data at baseline and at 1 month post-delivery of the new prostheses. Plaque samples were collected from intaglio surfaces of maxillary complete dentures at 1 month post-delivery to culture for any colonization of bacteria and/or yeasts. Results: There was a significant reduction in OHIP-EDENT scores within both treatment groups at the 1 month follow-up (p < 0.05). There was also a significant reduction in almost all OHIP-EDENT domains scores at 1 month. Gender was significantly associated with OHIP-EDENT score at baseline (p = 0.0419) and at 1 month (p = 0.0152). Female subjects tend to have higher OHIP-EDENT scores than male subjects. There was no significant difference in patient satisfaction between treatment groups both at baseline and at the 1 month visit for almost all aspects of satisfaction (p> 0.05). Appearance of maxillary denture was the only significant difference in patient satisfaction across treatment groups (p = 0.0213). The comparisons of microbial counts showed no significant difference between treatment groups. Conclusions: There were no significant difference on oral health-related quality of life (OHRQoL) and patient satisfaction between two treatment groups at baseline and 1 month. There was no significant difference in microbial counts between two treatment groups.