The aim of this report is to analyze the effects of high fluoride (F) intake on matrix metalloproteinase-2 (MMP-2), tissue inhibitors of metalloproteinase-1 (TIMP-1), and transforming growth factor-beta (TGF-beta) levels. Twenty-seven rabbits were divided into control and F groups. The control group comprised 11 rabbits that received distilled drinking water; the experimental group consisted of 16 rabbits that received distilled water with excessive F for 70 days. At the end of 70 days, serum F concentrations were evaluated, and the rabbits were then sacrificed. Bucco-lingual histological sections were obtained bilaterally from the mandibular bone. MMP-2, TIMP-1, and TGF-beta levels in the bone matrix were determined by immunohistochemical staining. The difference between the groups was evaluated with the Mann Whitney U test, and the intragroup difference in staining intensity was evaluated with Friedman and Wilcoxon tests. Increased mineralization and high bone turnover was observed in the fluorosis group. TGF-beta immunostaining of the mandibular bone in the experimental group was significantly more intense compared with that in the control group (p=0.03). MMP-2 and TIMP-1 staining were not statistically different between the experimental and the control groups (MMP-2, p=0.110; TIMP-1, p=0.479). Intra-group comparison revealed significant differences at MMP-2/TIMP-1 and TIMP-1/TGF-beta ratios only in F group (p=0.02 for MMP-2 and p=0.01 for TGF-beta). Excessive F uptake may affect bone remodeling process by increasing TGF-beta levels and TIMP/MMP and TIMP/TGF-beta ratios. Further studies including other bone regulating molecules are needed in order to explain bone metabolism in the presence of high doses of F.