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Clinical studies have identified advantages of digital complete denture technology including patient satisfaction, improved mastication, increased retention, and technique efficiency. However, studies that focus on the effect of denture adhesive on the retention of milled and heat-activated denture bases are lacking.The purpose of this clinical study was to evaluate the effectiveness of denture adhesive on the retention of milled and heat-activated denture bases.Twenty participants with complete maxillary edentulism were selected for this study (11 men and 9 women). Definitive impressions were obtained and scanned (iSeries impression scanner; Dental Wings). Digital data were sent to Global Dental Science for the fabrication of computer-aided design and computer-aided manufacturing (CAD-CAM) milled denture bases (MB condition). The physical impressions were poured in stone to produce casts for the fabrication of heat-activated acrylic resin denture bases (HB condition). A portable clinical motorized test stand and advance digital force gauge were modified to measure the amount of denture base retention in newtons. The denture bases were seated over the edentulous maxillary ridge and pulled 3 times vertically at 10-minute intervals without denture adhesive (MB and HB control conditions) and with denture adhesive (MBA and HBA test conditions). For statistical analysis, a repeated-measures ANOVA was performed (α=.05).The control MB condition had significantly higher retention values compared with all other conditions (P<.001). However, the use of adhesive significantly decreased the retention of the milled bases. No significant differences were found with or without the use of denture adhesive among heat-activated denture bases (P>.05).Significantly higher retention values were recorded with milled denture bases than heat-activated resin bases without the use of denture adhesive. However, denture adhesive did negatively affect the retention of milled complete dentures.