The involvement of reactive oxygen species in various diseases has been demonstrated almost in vitro or in animal studies and clinical studies supporting the involvement of reactive oxygen species are very few. Bilirubin has been recognized as an important antioxidant and also shown to have an inhibitory effect on the activity of NADPH oxidase, which may be an important source for superoxide production in various tissues. When the prevalence of vascular complcations was compared in diabetic patients with and without a congenital hyperbilirubinemia (Gilbert syndrome), the prevalence of retinopathy, macroalbuminuria and coronary artery disease in patients with Gilbert syndrome was about 20% of that in those without Gilbert syndrome. For study of lifestyle-related diseases, the Fukuoka Cohort was constructed from 2003 to 2009 in Kyushu area in Japan, which contains a total of 12,949 persons. Cross-sectional study of the Fukuoka Cohort revealed an inverse relation between serum bilirubin level and the prevalence of type 2 diabetes mellitus. A precursor of bilirubin, biliverdin-treated db/db mice exhibited less albuminuria and nephropathic changes. These effects were paralleled with normalization of oxidative stress markers and expression of NAD(P)H oxidase subunits in kidney. These results suggested that oxidative stress is an exacerbating factor of type 2 diabetes mellitus and that antioxidant therapies are of value to diabetic nephropathy.