The aim of this study was to compare the adaptation of complete denture base (CDB) manufactured by three different techniques: conventional, milling, and three-dimensional (3-D) printing. A master cast was duplicated to create 60 gypsum casts. Twenty casts (n = 20) were attributed to each group. In the computer-aided design and computer-aided manufacturing (CAD/CAM) groups (milling and 3-D printing), the 40 gypsum casts reserved for these two groups were scanned. An STL file was obtained and a master CDB was designed and then fabricated according to each technique. In the conventional group, a polyvinyl siloxane putty mold was obtained from the milled CDB, and this mold was used to fabricate 20 conventional denture bases by compression molding using the silicon-gypsum technique in a bronze flask. The inner surfaces of the obtained 60 CDB were scanned and superimposed over their corresponding master cast. Deviation analyses were calculated using digital subtraction technique. Five functional areas (posterior palatal seal, anterior border seal, crest of the ridge, maxillary tuberosities, and palate) were selected to evaluate the variations in CBD adaptation. Based on the results and color maps of all selected regions, milling technique offers the best adaptation. The crest of ridge in the conventional technique showed the least adaptation and the posterior palatal seal in the 3-D printing technique showed the best adaptation. Within the limitations of this study, the CAD/CAM fabrication techniques seem to offer better adaptation of CDB compared to the conventional fabrication technique. Milled CDBs presented the most homogeneous distribution of adaptation, yet the 3-D printing process seems a promising techniques that needs to be addressed and perfected. The CAD/CAM technologies can help overcome many limitations related to conventional impressions and therefore should be well investigated to improve the edentulous patient's quality of life.