OBJECTIVE: This study aimed to evaluate the biocompatibility of various fluoride agents using L929 fibroblast and human gingival fibroblast (HGF) cell cultures. MATERIALS AND METHODS: Five different fluoride agents were included in the study; 1.23% Acidulated Phosphate Fluoride (APF) gel (Sultan Health Care, Engle Wood, USA), 2% Sodium Fluoride (NaF) gel (Sultan Health Care, Engle Wood, USA), 1% Titanium Tetrafluoride (TiF₄) solution (Sigma-Aldrich(®) Chemie GmbH, Steinheim, Germany), 38% Silver Diamine Fluoride (SDF) solution (Saforide(®)-J. Morita; Toyo Seiyaku Kasei Ltd/Osaka-Japan), and 5% NaF varnish (Duraphat(®), Colgate Oral Pharmaceuticals, New York, NY, USA). Cytotoxicity was evaluated using the real-time xCELLigence system, while apoptotic activity was determined through Annexin V/PI and TUNEL assays. Genotoxicity was assessed using the micronucleus test. The expression levels of the pro-apoptotic marker BAX and the anti-apoptotic marker BCL-2 were quantified using real-time PCR. All experiments were performed in triplicate and independently repeated to ensure reproducibility, with data analyzed using non-linear regression for IC₠₀ determination, one-way ANOVA with Tukey's post hoc test for group comparisons, and chi-square or Fisher's Exact tests for categorical variables (SPSS 25.0); statistical significance was set at p < 0.05. RESULTS: NaF gel exhibited the lowest cytotoxicity in L929 fibroblast cell line, while APF gel demonstrated the least cytotoxicity in HGF cells. Both APF and NaF gels significantly induced apoptosis in L929 cells, with no notable apoptotic effects observed in HGF cells treated with these agents. Conversely, TiF₄ solution and NaF varnish consistently induced apoptosis across both cell lines, whereas SDF solution did not elicit significant apoptotic activity. In terms of genotoxicity, TiF₄ solution showed significant genotoxic effects, while SDF solution demonstrated the lowest genotoxic potential. The Bax/Bcl-2 ratios for all fluoride agents tested in the present study were found to be greater than 1, indicating that these agents induce apoptosis through the mitochondrial pathway, with a predominance of pro-apoptotic signals. CONCLUSIONS: Silver Diamine Fluoride, which gained substantial attention especially during the COVID-19 pandemic, has emerged as a highly effective and minimally invasive option for arresting caries and preventing early enamel lesions. With its rapid action and favorable safety profile, SDF solution is increasingly recognized as a superior alternative to commonly used topical fluoride agents, particularly in clinical settings where traditional dental procedures may carry heightened risks or present logistical challenges. CLINICAL RELEVANCE: This study provides critical insights into the biocompatibility profiles of commonly used fluoride agents, offering evidence-based guidance for their clinical application. Among the tested agents, SDF stands out for its minimal cytotoxicity and genotoxicity, coupled with its proven efficacy in caries arrest and enamel lesion prevention. By highlighting the distinct biocompatibility and apoptotic profiles of various fluoride agents, the findings support informed decision-making in selecting appropriate fluoride therapies to optimize patient safety and treatment outcomes.