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Immunological dysfunction has been suggested to play a major role in the pathogenesis of idiopathic granulomatous mastitis (IGM). We recently showed that ozone therapy was effective in patients with steroid-resistant IGM. This study assessed alterations in intracellular cytokine expression patterns in different T-lymphocyte subsets after ozone therapy in refractory IGM. Peripheral blood T lymphocyte subsets (CD8 + , CD4 + , CD4 + CD25 + CD127 - ) were analyzed via flow-cytometry for intracellular cytokine expressions IFN-γ, TNF-α, IL-10, and TGF-β before and after completion of 4-month systemic ozone therapy. Ozone therapy significantly increased the CD4 + IFN-γ + (p = 0.032), CD4 + TNF-α + (p = 0.028), and the CD8 + TNF-α + (p = 0.012) T cells. In contrast, significant decreases in CD4 + IL-10 + (p = 0.047) and CD8 + IL-10 + T cells (p = 0.022) and CD4 + CD25 + CD127 -//low Treg cells secreting TGF-β (p = 0.005) were found after ozone therapy. When patients were analyzed according to the response to ozone therapy, patients with a complete remission were more likely to have increased CD3 - CD16 + CD56 + natural killer cells (p = 0.0027) and decreased CD19 + B lymphocytes (p = 0.046) following ozone therapy. Our results suggest that ozone therapy stimulated a T-helper-1 response associated with IFN-γ production and downregulation of TGF-β expression in CD4 + CD25 + CD127 - Treg cells. These alterations in the immune system following ozone therapy can improve wound healing and restore immune dysfunction in patients with refractory IGM., (© 2022 International Federation for Cell Biology.)