INTRODUCTION: Osteonecrosis usually occurs with necrotic bone exposure in the mandible asymptomatically for long periods but can evolve to present pain, fistula, odor, bleeding, and suppuration. OBJECTIVE: To evaluate the influence of cyclosporine treatment and its influence on osteonecrosis in a rat model. METHODS: The animals were randomly divided into 05 groups (n = 8/group). The negative control group (SAL), positive control group treated with zoledronic acid (ZA + SAL), and test groups were treated with cyclosporine A (CsA) at 5, 2.5, and 1.25 mg/kg and treated with ZA. The left lower second molars were extracted. The animals were euthanized 1 month after tooth extraction. Digital radiographs, histological slides, and immunoexpression of IL-2, IL-6, TNF-α, PPAR-γ, c-Fos, c-Jun, FoxP3, and INF-γ were analyzed. Western blot assays were performed to investigate the expression of RORyT. In addition, hematological analysis, body mass variation, and femur mechanical tests were performed. RESULTS: Radiographs showed that in the groups treated with ZA, there was an increase in the radiolucent area suggestive of osteonecrosis, and treatment with cyclosporine did not reduce this parameter (p <
0.001). In the western blot analysis, animals treated with ZA showed increased expression of RORyT (1.887 ± 0.114) compared to the saline group (0.799 ± 0.107), and treatment with the highest dose of cyclosporine (0.652 ± 0.070) reduced this expression (p <
0.001). DISCUSSION: Studies have observed bone health in animals treated with CsA. Treatment with this immunosuppressant showed a bone-protective effect of CsA, which corroborates our findings. CONCLUSION: Treatment with CsA reduced the immunoexpression of pro-inflammatory cytokines such as IL-2 and TNF-α and decreased the expression of RORyT.