Antioxidants could be a therapy against obesity. We investigated whether a melon juice extract rich in superoxide dismutase activity would prevent its development in hamsters. Three groups received either a standard diet or a high fat diet (HF) plus a daily gavage with water (Control) or extract. After 12 weeks, the extract lowered triglyceridemia (67 percent), liver superoxide anion production (11 percent), lipid and protein oxidation products (35 and 35.7 percent), leptinemia (29 percent) and increased adiponectinemia (22 percent), leading to a concomitant reduction in insulinemia (39 percent), insulin resistance (41 percent) and abdominal lipids (28 percent). It decreased liver lipids (71 percent) and fully prevented the steatohepatitis induced by HF diet. Functional foods containing this melon extract could be an important new therapy to prevent obesity.