Nearly 200 million people in the world including 40-70 million in Bangladesh have been exposed to arsenic from drinking water and thus at increased risk of skin and other cancers for their lifetime. The most likely mechanism underlying this arsenic-induced risk is oxidative stress mediated DNA and cellular damage. To identify an effective preventive approach for this increased risk we established the Bangladesh vitamin E and selenium Trial (BEST)-a 2W2 factorial randomized chemoprevention trial (RCT) for evaluating whether long- term vitamin E or selenium supplementation prevents non-melanoma skin cancer (NMSC) risk and alters oxidative stress markers in peripheral tissues in a uniquely exposed population. In 2005, we were awarded funding for the first 5 years of this 10-year study. The goal of the first funding period was to design BEST and identify, recruit, and randomize 4,444 individuals with arsenic-related skin lesions into 4 treatment arms: vitamin E only (100 IU/day), L-selenomethionine only (200 5g/day), both vitamin E and selenium, and placebo. To ensure the successful completion of the study, we have exceeded our recruitment target by 80% and randomized 7,000 individuals. In the proposed 5 years of the study (7/1/2010-6/30/2015), we will complete the study through continued intervention for 6 years, follow-up (including a post-intervention period), collection of questionnaire and clinical data, and biological samples at various time points, and finally statistical analyses and report writing of the final dataset. In view of current concerns regarding a possible diabetogenic effect of selenium supplementation, we now include a new specific aim to specifically assess treatment effects on that endpoint, in addition to our originally proposed endpoints of NMSC and mortality. Finally, as an extension of our ongoing evaluation of the current specific aim to examine treatment effects on oxidative stress markers, especially 8-OHdG, in peripheral tissues (blood and urine), we now also include an aim to more comprehensively and specifically evaluate treatment effects on a panel of oxidative stress markers measured in normal skin and NMSC tissues-the target tissues of our primary clinical endpoint. Overall, BEST will be a highly efficient and unique RCT, able to evaluate effects of vitamin E and selenium supplementation on prevention of skin cancer and other health outcomes and will create a valuable research resource for future prevention, clinical and molecular research.