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Dental laboratories use different computer-aided design and computer-aided manufacturing (CAD-CAM) systems to fabricate fixed prostheses; however, limited evidence is available concerning which system provides the best marginal discrepancy.The purpose of this in vitro study was to evaluate the marginal fit of 5 different monolithic zirconia restorations milled with different CAD-CAM systems.Thirty monolithic zirconia crowns were fabricated on a custom-designed stainless steel die and were divided into 5 groups according to the type of monolithic zirconia crown and the CAD-CAM system used: group TZ, milled with an MCXL milling machine; group CZ, translucent zirconia milled with a motion milling machine; group ZZ, zirconia milled with a dental milling unit; group PZ, translucent zirconia milled with a zirconia milling unit; and group BZ, solid zirconia milled using an S1 VHF milling machine. The marginal fit was measured with a binocular microscope at an original magnification of ×100. The results were tabulated and statistically analyzed with 1-way ANOVA and post hoc surface range test, and pairwise multiple comparisons were made using Bonferroni correction (α=.05).The type of CAD-CAM used affected the marginal fit of the monolithic restoration. The mean (±SD) highest marginal discrepancy was recorded in group TZI at 39.3 ±2.3 μm, while the least mean marginal discrepancy was recorded in group IZ (22.8 ±8.9 μm). The Bonferroni post hoc test showed that group TZI was significantly different from all other groups tested (P<.05).Within the limitation of this in vitro study, all tested CAD-CAM systems produced monolithic zirconia restorations with clinically acceptable marginal discrepancies; however, the CAD-CAM system with the 5-axis milling unit produced the best marginal fit.