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Titanium (Ti) and zirconium (Zr) have gained attention for their promising properties in medical and dental applications, including their biocompatibility and antimicrobial effects. Denture base resins primarily made of polymethyl methacrylate (PMMA), often face issues such as microbial adhesion and limited bioactivity. Incorporating Ti and Zr into these resins could enhance their biological properties. This study investigates the biocompatibility and antimicrobial efficacy of Ti- and Zr-infused denture base resins compared to conventional PMMA resins. Three groups of denture base resins were prepared: Group A (PMMA control), Group B (PMMA + 5 wt% Ti) and Group C (PMMA + 5 wt% Zr). Biocompatibility was assessed by culturing human gingival fibroblasts (HGFs) on resin samples and performing an MTT assay to evaluate cell viability over 72 hours. Antimicrobial properties were tested against <i>Streptococcus mutans</i> and Candida albicans using a colony-forming unit (CFU) assay. Statistical analysis was performed using ANOVA with a significance level of p < 0.05. Group B (Ti-infused) exhibited a 25% increase in cell viability compared to the control group, with cell viability reaching 85% after 72 hours. Group C (Zr-infused) showed a 15% increase in cell viability. Both Ti and Zr groups demonstrated significant antimicrobial activity. Group B showed a 60% reduction in <i>S. mutans</i> CFU and a 45% reduction in <i>C. albicans</i> CFU, while Group C showed a 40% reduction in <i>S. mutans</i> and a 30% reduction in <i>C. albicans</i>. Ti- and Zr- infused denture base resins demonstrate improved biocompatibility and antimicrobial properties compared to conventional PMMA. Titanium, in particular, provides superior biological outcomes, suggesting its potential for enhancing denture base materials. These findings support the incorporation of Ti and Zr in future dental materials to improve patient outcomes.