In most people, nicotine is extensively (70% to 80%) metabolized to cotinine by C-oxidation. In a clinical trial, a 57-year-old woman was found to have the expected plasma levels of nicotine but unusually low plasma levels of cotinine both when smoking cigarettes and while receiving transdermal nicotine. To characterize her metabolism, simultaneous infusions of deuterium-labeled nicotine (d2) and cotinine (d4) were administered, with comparison to 20 other control smokers. The clearance of nicotine was unusually low (6.5 ml/min/kg versus 17.2 ml/min/kg), and the half-life of nicotine significantly longer (348 minutes versus 138 minutes) in the index case subject compared with the control subjects. The clearance of cotinine was normal. The index case subject converted only 9% of nicotine to cotinine, compared with 72% for the control subjects. As far as we know, this is the first person with deficient C-oxidation of nicotine to be characterized. Deficient C-oxidation of nicotine is associated with a long half-life of nicotine and deficient generation of cotinine, both of which could influence the risks and addictiveness of tobacco use in affected individuals.