OBJECTIVE: This study was undertaken to evaluate the antioxidant effects of lycopene in physiological doses and its possible effects on the immune response in patients with Type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: A total of 35 patients with T2DM of both sexes aged 54+/-9 yr were enrolled in a double-blind placebo-controlled clinical trial conducted for 2 months. After a 2-week lycopene-free diet washout period, patients were allocated to either lycopene supplementation group (10 mg/day) (no.=16) or placebo group (no.=19), which were age- and sex matched. Patients were instructed to keep their diet and physical activity as unchanged as possible. RESULTS: While dietary intake of energy and body weight did not change, the ratio of serum total antioxidant capacity (TAC) to malondialdehyde (MDA) increased significantly in the lycopene group compared to the placebo group (p=0.007). Though a statistically significant increase in serum concentrations of lycopene (p<0.001) was not accompanied by enhanced delayed-type hypersensitivity response, a significant negative correlation was found between serum levels of lycopene and immunoglobulin (Ig)G (r=-0.338, p=0.008). Interestingly, variations of serum levels of lycopene directly correlated with those of IgM (r=0.466, p=0.005). There was an insignificant decrement in serum anti-oxidized LDL IgG levels in the lycopene group. CONCLUSIONS: Lycopene, probably by increasing TAC and inhibiting MDA-LDL formation, may attenuate T cell-dependent adaptive (pro-atherogenic) immune response. Meanwhile, with enhancement of innate immunity and hence prevention of ox-LDL uptake by macrophage and foam cell formation, lycopene may be effective in prevention of long-term diabetic complications, notably cardiovascular disease.