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Factors that may affect the marginal adaptation of computer-aided design and computer-aided manufacturing (CAD-CAM) restorations include preparation design, impression technique, and CAD-CAM system. The influence of impression technique and preparation design on CAD-CAM partial coverage restorations has not been fully addressed.The purpose of this in vitro study was to investigate the influence of direct and indirect digital scanning techniques and 2 preparation designs on the marginal adaptation of CAD-CAM onlays.Two mesio-occlusal buccal onlay preparations with reduction of the mesiobuccal cusp were made: conventional preparation (CP) with a 1.2-mm modified shoulder margin and modified preparation (MP) flat cuspal reduction without shoulder. Virtual models were generated from each preparation by using a digital scanner (BlueCam; Dentsply Sirona) from the plastic teeth (direct digital scan) or from the stone dies (indirect digital scan). Onlays were designed using a CAD-CAM system (CEREC 4.0; Dentsply Sirona), and nanoceramic resin blocks (Lava Ultimate Restorative; 3M ESPE) were milled using the CEREC MCX milling machine. Marginal discrepancy was evaluated using an optical stereomicroscope at ×25 magnification in 18 locations distributed along the margins of the preparation. The data were analyzed by using 3-way ANOVA followed by the Tukey HSD test (α=.05).CP presented a statistically significant reduced average marginal adaptation (59 ±50 μm) than did MP (69 ±58 μm) (P<.001). The Tukey HSD test showed the presence of a significantly larger marginal discrepancy in the mesial and buccal locations of MP when compared with CP. Regarding impression techniques, the buccal location presented the smallest average marginal discrepancy in restorations fabricated with indirect impression when compared with direct impression (42 ±33 μm and 60 ±39 μm) (P<.001).The results showed that conventional preparation with a modified shoulder margin presented improved marginal adaptation compared with modified preparation with flat cuspal reduction. Direct and indirect digital scanning techniques produced restorations within a clinically acceptable range; however, the indirect scanning technique resulted in the fabrication of restorations with superior marginal adaptation on the buccal location.