That nicotine addiction sustains tobacco use for most smokers is well established. Once a person is addicted to nicotine, quitting smoking is difficult, and more than 90% of smokers who try to quit each year fail. It follows that an important component of a policy to reduce tobacco use in the population is to prevent development of nicotine addiction in young people. Young people do not start to smoke because they are addicted, but once they begin to smoke they become addicted, which sustains smoking into adulthood. It is difficult to prevent adolescents from experimenting with cigarettes; however, by reducing the content of nicotine in tobacco products, it may be possible to prevent the transition from experimental smoking to addiction. Governmental regulation of tobacco, and of nicotine in particular, is being considered by legislators in the United States Congress and in a number of other countries around the world. A widely discussed proposal is the gradual reduction of the nicotine content of all cigarettes to a level that does not sustain nicotine addiction. Such a cigarette could prevent adolescents from becoming addicted, and might also serve to wean adult smokers to a lower level of addiction and, therefore, facilitate quitting. Of concern with such a policy is whether compensatory oversmoking of cigarettes will be harmful to already addicted smokers. This proposal aims to continue research on the safety of reducing the nicotine content of cigarettes gradually. Work conducted during the previous project period has shown that the concept is feasible and that compensatory oversmoking is not a problem, at least in the short term. The present proposal examines the question of whether a reduced intake of nicotine can be sustained for a prolonged period of time without more compensatory oversmoking, and the cardiovascular consequences of such a reduction. Volunteer smokers will smoke research cigarettes with progressively reduced nicotine content over 6 months after which the lowest yield cigarettes will be continued for an additional 6 months. Subjects will then be followed for an additional year to assess long-term changes in smoking behavior. Periodic assessments will be made of exposure to tobacco smoke nicotine, gas and tar, using the biomarkers of blood and urinary cotinine, urinary nicotine and metabolites, carboxyhemoglobin, urinary NNAL, metabolites of polycyclic aromatic hydrocarbons (PAH), urinary mercapturic metabolites, as well as cardiovascular markers of coagulation, inflammation, and endothelial function. The proposed research is needed to guide governmental regulators as to how best to regulate nicotine in cigarettes and is an essential first step in examining the feasibility of a national regulation program.