PURPOSE: . Microstructural and physico-mechanical characterization of highly translucent zirconia, prepared by milling technology (CAD-CAM) and repeated firing cycles, was the main aim of this in vitro study. MATERIALS AND METHODS: . Two groups of samples of two commercial highly-translucent yttria-stabilized dental zirconia, VITA YZ-HTWhite (Group A) and Zolid HT + White (Group B), with dimensions according to the ISO 6872 “Dentistry - Ceramic materials”, were prepared. The specimens of each group were divided into two subgroups. The specimens of the first subgroups (Group A1 and Group B1) were merely the sintered specimens. The specimens of the second subgroups (Group A2 and Group B2) were subjected to 4 heat treatment cycles. The microstructural features (microstructure, density, grain size, crystalline phases, and crystallite size) and four mechanical properties (flexural strength, modulus of elasticity, Vickers hardness, and fracture toughness) of the subgroups (i.e. before and after heat treatment) were compared. The statistical significance between the subgroups (A1/A2 , and B1/B2) was evaluated by the t-test. In all tests, P values smaller than 5% were considered statistically significant. RESULTS: . A homogenous microstructure, with no residual porosity and grains sized between 500 and 450 nm for group A and B, respectively, was observed.Crystalline yttria-stabilized tetragonal zirconia was exclusively registered in the X-ray diffractograms. The mechanical properties decreased after the heat treatment procedure, but the differences were not statistically significant. CONCLUSION . The produced zirconia ceramic materials can be safely (i.e., according to the ISO 6872) used in extensive fixed prosthetic restorations, such as substructure ceramics for three-unit prostheses involving the molar restoration and substructure ceramics for prostheses involving four or more units. Consequently, milling technology is an effective manufacturing technology for producing zirconia substructures for dental fixed all-ceramic prosthetic restorations.