Background: Although tobacco products with reportedly reduced carcinogen content are being marketed, carcinogen uptake in people who use these products has not been assessed systematically. Methods: Between June 2001 and November 2002, 54 users of smokeless tobacco and 51 cigarette smokers were randomly assigned to one of two groups. One used test products (Swedish snus for users of smokeless tobacco or OMNI cigarettes for smokers), while the other quit and used medicinal nicotine (the nicotine patch). All participants were assessed for urinary levels of total NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide], metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Smokers were also assessed for levels of 1-hydroxypyrene (1-HOP), a biomarker of polycyclic aromatic hydrocarbon uptake. Assessments were made weekly during 2 weeks of baseline normal tobacco use and 4 weeks of treatment. Statistical tests were two-sided. Results: Primary data analyses were conducted on 41 users of smokeless tobacco and 38 cigarette smokers who met the inclusion criteria. Total NNAL levels were statistically significantly lower in users of smokeless tobacco after they switched to snus or to nicotine patch (P<.001 for both groups) than they were before the switch, although the overall mean total NNAL level among subjects who used the nicotine patch was statistically significantly lower than that among those who used snus (mean = 1.2 and 2.0 pmol of NNAL/mg of creatinine, respectively; mean difference = 0.9 pmol of NNAL/mg of creatinine, 95% confidence interval [CI] = 0.2 to 1.5; P = .008). Compared with baseline levels, total NNAL levels (P = .003), but not 1-HOP levels, were statistically significantly reduced in cigarette smokers who switched to the OMNI cigarette, although both total NNAL levels and 1-HOP levels were statistically significantly reduced in smokers who switched to the nicotine patch (P<.001 for both). The overall mean total NNAL levels among smokers who used the nicotine patch was statistically significantly lower than that among smokers who used the OMNI cigarette (mean = 1.2 and 1.9 pmol of NNAL/mg of creatinine, respectively; mean difference = 0.6 pmol of NNAL/mg of creatinine, 95% CI = 0.1 to 1.1; P = .022). Conclusion: Switching to reduced-exposure tobacco products or medicinal nicotine can decrease levels of tobacco-associated carcinogens, with greater reductions being observed with medicinal nicotine. Medicinal nicotine is a safer alternative than modified tobacco products.