Interferon-alpha (IFN-alpha) has extremely broad effects on the immune system, and the influence of IFN-alpha on regulatory T (Treg) cells is not fully known. In this report, Treg cells were analyzed in patients with metastatic renal cell carcinoma (RCC) following IFN-alpha monotherapy or treatment with IFN-alpha and interleukin (IL)-2. CD4(+) and FoxP3(+) Treg cells were significantly decreased for 2 weeks after the initiation of IFN-alpha monotherapy, but recovered later as treatment proceeded. Patients treated with both IFN-alpha and IL-2 increased their Treg cell levels during the first 2 weeks after initiation of treatment. Patients who derived complete response (CR), partial response (PR), or stable disease (SD) from IFN-alpha monotherapy had lower Treg cell levels before treatment than did patients whose disease progressed. Low Treg cell levels before treatment may therefore be advantageous to subsequent immunotherapy with IFN-alpha, and predictive for treatment results in RCC patients.