Mitochondrial dysfunction and increased production of reactive oxygen species (ROS) may have a key role in the pathogenesis of several cancers, including colorectal cancer. Extensive studies have shown mitochondria to be the predominant endogenous source of ROS in cells. Increased ROS exposure induces oxidative DNA damage in mitochondrial and nuclear DNA as well as the activation of apoptotic and inflammation pathways. Through these activities, ROS exposure can lead to malignant transformation of cells. The extent of oxidative damage and malignant transformation is influenced by the activity of the ROS detoxification system. Subtle changes in ROS production and detoxification are influenced by environmental factors and genetic variation between individuals. While these activities are well established in cellular and animal studies, few human studies have evaluated the relationship between mitochondrial dysfunction and colorectal cancer risk. We will prospectively evaluate the association between several aspects of mitochondrial dysfunction, genetic variation, oxidative damage and the ROS detoxification system and colorectal cancer in a frequency matched nested case-control study of 640 colorectal cancer cases and 1280 controls within a well-established prospective cohort, the Singapore Chinese Health Study. Indicators of mitochondrial dysfunction include mitochondrial DNA copy number, mitochondria DNA damage as measured by quantitative real time polymerase chain reaction and oxidative damage as measured by urinary F2-isoprostanes and plasma fluorescent oxidation products. The mitochondrial genome and nuclear genes related to mitochondrial biogenesis will be evaluated for genetic susceptibility to oxidative stress through the measurement of polymorphisms and haplogroups. Additional major determinants of oxidative stress that will be measured include antioxidant enzymes of the ROS detoxification system, dietary intake of fruits and vegetables and more specifically by plasma carotenoids. Together, these measures provide a multi-pronged and integrated approach that addresses major aspects of mitochondrial dysfunction and oxidative stress that can be analyzed in humans. It will provide valuable information on the role of mitochondrial dysfunction and the mitochondrial related genetic variation in the risk of colorectal cancer, which will aid in the identification of high risk individuals and may provide novel opportunities for prevention of colorectal cancer.