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Abstract: To determine whether conventional hyperthermia (42–45°C) or ablation therapy (>50°C) achieves better synergistic effects on direct cytotoxicity and anti-tumor immunity, we compared the therapeutic effects of two hyperthermia temperatures, 43 and 55°C, in terms of cytotoxicity and upregulation of immune functions in a mouse malignant melanoma model. Melanoma-bearing mice were treated by directly applying regional hyperthermia to the tumor nodule with a heating light at a temperature of 43°C for 30min or 55°C for 10min. The tumor growth curve and mice survival rate were observed. To investigate the hyperthermia-induced immunological response, peripheral blood CD4+ and CD8+ T cells and the serum IL-2 level were determined. Our results indicated that application of regional hyperthermia at the ablation temperature (such as 55°C) achieved better synergistic anti-tumor effects than did conventional hyperthermia (43°C). Significant increases in the number of peripheral blood CD4+ T cells and the serum IL-2 level likely contributed to the underlying mechanism. [Copyright &y& Elsevier]