STATEMENT OF PROBLEM: High-translucency zirconia and lithium disilicate are among the most used materials in contemporary fixed prosthodontics because of their excellent esthetic and mechanical properties. However, their different cementation techniques, physical properties, and biocompatibility profiles can influence the clinician's choice. PURPOSE: The purpose of this in vitro study was to evaluate the mechanical strength and adhesive cementation techniques for zirconia and lithium disilicate materials through mechanical testing, including compressive and pull-out tests. The biocompatibility of these materials was also assessed. MATERIAL AND METHODS: A total of 72 human maxillary molars that were free from damage were embedded in acrylic resin and prepared 1 mm occlusal to the enamel-cementum junction. The specimens were divided into 3 groups: lithium disilicate (CAD), zirconia High-Translucency HT (CAD), and lithium disilicate (PRESS). Following the recommended cementation protocols, compression and pull-out tests were performed. Twelve disks of each group were fabricated to test the integration of gingival fibroblasts. Human gingival fibroblasts were isolated from gingival biopsies and cultured in Dulbecco modified Eagle medium (DMEM). Cell viability was determined using the 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, serving as an indicator of cellular respiration. RESULTS: Zirconia was the most mechanically efficient material, with a high resistance value (2081.4 ±405.4 N). The pull-out test determined that CAD-CAM lithium disilicate had similar adhesive cementation strength (244.3 ±29.3 N) to the other groups. In terms of biocompatibility, all materials demonstrated good results, with lithium disilicate CAD emerging as the most biocompatible material. Statistically significant differences were observed between the zirconia HT material and lithium disilicate PRESS (P=.006) and between lithium disilicate CAD and lithium disilicate PRESS (P=.002). CONCLUSIONS: All the monolithic restorations analyzed have shown excellent results in terms of mechanical properties, adhesion, and biocompatibility. Zirconia exhibited outstanding mechanical properties, making it an ideal choice for applications requiring high strength. To achieve adhesion results comparable with those of lithium disilicate, a protocol using airborne-particle abrasion and silane with 10-MDP is recommended. This approach ensures optimal adhesion, enhancing the longevity and effectiveness of the restoration.