Background: Limited data are available on carcinogen uptake in smokers who reduce their smoking. To determine whether reducing the number of cigarettes smoked per day would lead to a corresponding reduction in carcinogen uptake, we measured levels of metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the urine of smokers who reduced their smoking for up to 26 weeks. Methods: We recruited 153 smokers, of whom 151 were randomly assigned to a reduction group or a waitlist group. In the reduction group of 102 smokers, we measured the metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Gluc) at two baseline times and at weeks 4, 6, 8, 12, and 26 after baseline. Smokers were then expected to reduce their number of cigarettes per day by 25% in weeks 0-2, 50% in weeks 2-4, and 75% in weeks 4-6 and to maintain the reduced level through week 26. In the waitlist group of 49 smokers, four baseline measurements over 7 weeks were made to assess the longitudinal stability of the metabolite measurements, and then the smokers began the reduction program. All statistical tests were two-sided. Results: For waitlist and reduction groups results were comparable. Statistically significant reductions in the lung carcinogen metabolites were observed at most intervals as smokers reduced the number of cigarettes smoked each day. However, the observed decreases were generally modest, always proportionally less than the reductions in cigarettes smoked per day, and sometimes transient. For example, among the 65 individuals in the reduction group who reduced cigarettes per day by 40% or more during weeks 4-12 after baseline, mean decreases in cigarettes per day were 53% (week 4), 74% (week 6), 75% (week 8), and 74% (week 12); whereas the corresponding mean reductions in NNAL plus NNAL-Gluc were 29%, 33%, 37%, and 29%. (P<.001 for all NNAL plus NNAL-Gluc values) Conclusions: Statistically significant reductions in levels of urinary metabolites of a tobacco-specific lung carcinogen were achieved by reduction in smoking, but for most smokers, reductions were modest and transient.