Objective: Sintering is a critical step in fabricating 3D-printed zirconia (3Dp/ZrO2) restorations and is significantly influenced by gravity. Additionally, the layer-by-layer structure of 3Dp/ ZrO2 introduces anisotropy. Therefore, this study aims to investigate the influence of sintering placement orientation on the mechanical properties and microstructure of 3Dp/ZrO2. Materials and Methods: A digital light processing-type 3D printer and ZrO2 slurry were used to fabricate green bodies, after which one-step sintering was used to create sintered 3Dp/ ZrO2 products. Group-A: Sintered with the printing layer orientation parallel to the horizontal plane. Group-B: Sintered with the printing layer orientation perpendicular to horizontal plane, with the short axis aligned vertically. Group-C: Sintered with the printing layer orientation perpendicular to horizontal plane, with the long axis aligned vertically. Shrinkage ratio, bulk density, three-point and biaxial flexure tests, scanning electron microscopy with energy dispersive spectrometry, X-ray diffraction, and micro-computed tomography were used to determine the physical, mechanical, and microstructural properties of the sintered 3Dp/ZrO2 specimens. Results: Group-B (558.28 102.01 MPa) and Group-C (423.47 38.46 MPa) showed a significantly lower flexure strength than Group-A (789.25 57.10 MPa). More grain boundary defects and microdefects were observed in Group-B and Group-C. Different sintering placement orientations did not cause significant differences in shrinkage ratio, density, phase, or grain size. Conclusions: The sintering placement orientation of 3Dp/ZrO2 influenced its mechanical properties and microstructure. Sintering with the printing layer orientation parallel to horizontal plane showed superior mechanical properties. In contrast, the perpendicular orientation showed compromised performance, likely due to loose grain boundaries and internal microdefects observed within 3Dp/ZrO2. Clinical Significance: This study provides practical guidance for dental professionals by demonstrating how sintering placement orientation affects the microstructure of 3Dp/ZrO2. Considering placement orientation during sintering process can help reduce defects and improve the mechanical properties of zirconia-based restorations for better clinical outcomes. (c) 2025 The Authors. Published by Elsevier Inc. on behalf of FDI World Dental Federation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)