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Abstract Objective To evaluate the influence of RORγT inhibition by digoxin on inflammatory changes related to interleukin-17 (IL-17) in the pulp of rats treated with zoledronate (ZOL). Methodology Forty male Wistar rats were divided into a negative control group (NCG) treated with saline solution, a positive control group (PCG) treated with ZOL (0.20 mg/kg), and three groups treated with ZOL and co-treated with digoxin 1, 2, or 4 mg/kg (DG1, 2, and 4). After four intravenous administrations of ZOL or saline solution in a 70-day protocol, the right molars were evaluated by histomorphometry (number of blood vessels, blood vessels/µm2, cells/µm2, total blood vessel area, and average blood vessel area) and immunohistochemistry (IL-17, TNF-α, IL-6, and TGF-β). The Kruskal-Wallis/Dunn test was used for statistical analysis. Results PCG showed an increase in total blood vessel area (p=0.008) and average blood vessel area (p=0.014), and digoxin treatment reversed these changes. DG4 showed a reduction in blood vessels/µm2 (p<0.001). In PCG odontoblasts, there was an increase in IL-17 (p=0.002) and TNF-α (p=0.002) immunostaining, and in DG4, these changes were reversed. Odontoblasts in the digoxin-treated groups also showed an increase in IL-6 immunostaining (p<0.001) and a reduction in TGF-β immunostaining (p=0.002), and all ZOL-treated groups showed an increase in IL-17 (p=0.011) and TNF-α (p=0.017) in non-odontoblasts cells. Conclusion ZOL induces TNF-α- and IL-17-dependent vasodilation and ectasia, and the classical Th17 response activation pathway does not seem to participate in this process. interleukin17 interleukin 17 interleukin-1 IL17 IL (IL-17 ZOL. . (ZOL) NCG (NCG (PCG 0.20 020 0 20 (0.2 mg/kg, mgkg , mg kg mg/kg) cotreated co 1 2 DG1, DG1 DG (DG1 4. 4) 70day day 70 protocol number vessels vesselsµm2 vesselsµm µm2 µm cellsµm2 cellsµm cells cells/µm2 IL17, 17, TNFα, TNFα TNF α, α IL6, IL6 6, 6 TGFβ. TGFβ TGF β TGF-β) KruskalWallis/Dunn KruskalWallisDunn Kruskal Wallis/Dunn Wallis Dunn analysis p=0.008 p0008 p 008 (p=0.008 p=0.014, p0014 p=0.014 014 (p=0.014) vessels/µm p<0.001. p0001 p<0.001 001 odontoblasts IL-1 p=0.002 p0002 002 (p=0.002 digoxintreated IL- (p<0.001 p=0.002, ZOLtreated p=0.011 p0011 011 (p=0.011 p=0.017 p0017 017 (p=0.017 nonodontoblasts non IL17dependent ILdependent dependent ectasia Th Th1 process interleukin1 interleukin- IL1 (IL-1 (ZOL 0.2 02 (0. (DG 7 cells/µm KruskalWallis WallisDunn p=0.00 p000 00 (p=0.00 p001 p=0.01 01 (p=0.014 p<0.00 (p<0.00 (p=0.01 (IL- 0. (0 p=0.0 p00 (p=0.0 p<0.0 (p<0.0 (IL ( p=0. p0 (p=0. p<0. (p<0. p=0 (p=0 p<0 (p<0 p= (p= p< (p< (p