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Introduction Fever-induced mild heat stress plays an important role in cellular responses. The best-known heat shock response is heat shock protein (HSP) secretion. We investigated the effect of mild heat stress on serum HSP70 levels and a possible association between the immune system and these molecules by applying a mild heat stress model using a thermal water bath. Method Peripheral blood samples from 16 osteoarthritis (OA) patients who were treated with 39–40 °C thermo-mineral water immersion were examined. Samples were drawn before the first bath, after the first bath, and at the end of treatment. HSP70 levels and interferon-gamma (IFN)-γ responses in peripheral blood mononuclear cells (PBMC) were evaluated in plasma by enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot (ELISPOT) assay, respectively. Results IFN-γ-secreting PBMC numbers were increased significantly in response to HSP70, purified protein derivative (PPD), and phytohemagglutinin (PHA) stimulation after the first bath, as compared to before bathing values (p = 0.005, p = 0.012, p = 0.021). HSP level in serum was also increased after the first bath, and decreased to near-baseline levels after treatment, however the differences were not significant. Conclusions The initial increase in HSP 70 and IFN-γ levels after the first bath and the final decrease at the end of serial baths suggest that the immune system adapts to the heat stress at the end of this intervention. [ABSTRACT FROM AUTHOR]