GPX1 encoding the enzyme glutathione peroxidase 1 (GPX1) and hOGG1 encoding the 8-oxoguanine glycosylase 1 (OGG1) may counteract oxidative stress and resulting DNA damage associated with lifestyle-related exposures. We examined whether the polymorphisms GPX1 Pro(198)Leu and OGG1 Ser(326)Cys or low erythrocyte GPX enzyme activity in pre-diagnostic blood samples are associated with colorectal cancer risk, and assessed possible interactions between the polymorphisms or enzyme activity and various lifestyle factors in relation to colorectal cancer risk. Additionally, we studied whether the GPX1 Pro(198)Leu polymorphism and several lifestyle factors predict GPX activity in erythrocytes. The present study was nested within the prospective "Diet, Cancer and Health" study of 57,053 Danes including 375 colorectal cancer cases and a comparison group of 779 individuals matched on gender. Biomaterial was sampled and information on lifestyle factors was obtained from questionnaires filled in at enrolment in 1993-1997. GPX1 Pro(198)Leu, hOGG1 Ser(326)Cys and erythrocyte GPX enzyme activity were not associated with risk of colorectal cancer. We observed a higher risk associated with alcohol consumption and smoking among homozygous GPX1(198)Leu carriers, with incidence rate ratios for colorectal cancer of 1.45 (95% CI: 1.17-1.81, P=0.02) per 10g alcohol intake per day and 2.56 (95% CI: 0.99-6.61, P=0.02) among ever smokers compared with never smokers at enrolment. Erythrocyte GPX activity was influenced by the GPX1 Pro(198)Leu genotype, gender, smoking intensity, and intake of fruits and vegetables. Our results indicate that lifestyle-related oxidative stress may be a risk factor for colorectal cancer among subjects with a lowered defence.