Interleukin-2 (IL-2) is currently used to treat patients with metastatic renal cell carcinoma and malignant melanoma. Clinical use of IL-2 is limited by severe side effects, particularly hypotension. Because of such dose-limiting side effects, the full period of IL-2 dosing is frequently curtailed. Our study demonstrates that M40403, a synthetic superoxide dismutase mimetic (SODm), which catalytically remove superoxide anions, reversed IL-2 induced hypotension in a murine model. M40403 allowed the dose of IL-2 to be increased significantly. Reversal of hypotension was attributed to inhibition of superoxide-driven deactivation of endogenously released catecholamines. Furthermore, M40403 increased IL-2 induced lymphocyte cytotoxicity both in vitro and in vivo. This appeared to relate to effects on macrophage-produced superoxide. Enhanced cytotoxic lymphocyte activation by IL-2 plus M40403 appeared to correlate with enhancement of IL-2 induced tumor responses against Meth A spindle cell ascites tumor. The combination of IL-2 and M40403 induced 50% complete remissions, lasting >120 days compared to untreated mice (15 day median survival), or mice treated with IL-2 (21 day median). M40403 also increased the response of subcutaneous RENCA renal carcinoma implants to IL-2 treatment. These results establish that M40403 inhibits the dose limiting hypotension due to IL-2 through a novel mechanism while enhancing anti-cancer activity.