Statement of Problem: Three-dimensionally (3D) printed acrylic resin base materials have been adopted in prosthetic dentistry. However, their mechanical and biological properties require improvement., Purpose: The purpose of this clinical study was to evaluate the effect of adding zirconium oxide nanoparticles to a 3D printable acrylic resin base material for a 2-implant-retained complete mandibular overdenture in terms of peri-implant tissue health, surface roughness, and biofilm formation., Material and Methods: Twenty edentulous patients were enrolled in this clinical parallel study. All patients received maxillary complete dentures opposing a 2-implant-retained mandibular overdenture. The participants were randomly divided into 2 equal groups according to the mandibular overdenture base material, nonmodified 3D printable acrylic resin (control group) or 3D printable acrylic resin base material modified with 3.0 wt% zirconium oxide nanoparticles (study group). Peri-implant tissue health and surface roughness were measured immediately at the insertion of the mandibular overdenture (T0), after 3 months (T1), and after 6 months (T2). Microbiological assessment of the denture base was done after 1 week, 1 month, 3 months, and 6 months of overdenture use. The data were analyzed using a statistical software program. The Wilcoxon signed-rank test, paired t test, and Fisher exact test were used to compare distributed data. The Mann Whitney U test and repeated measures ANOVA test were used to compare distributed data at different times (α=.05)., Results: The gingival index (GI), plaque index (PI), probing depth (PD), and surface roughness values at the baseline, 3 months, and 6 months were statistically higher with the nonmodified compared with the modified group (P=.001). Regarding the microbiological analysis, the nonmodified group also had a statistically higher mean bacterial and Candida albicans count than the modified group (P<.05). No significant increase in the bacteria was found in the nonmodified group with time (P=.252), but, for the modified group, a statistically significant decrease in bacteria count was found with time (P<.001)., Conclusions: Adding zirconium oxide nanoparticles to a 3D printable acrylic resin base material was found to be promising. This addition improved the peri-implant tissue health and decreased surface roughness and biofilm formation., (Copyright © 2024 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)