Currently, smokeless tobacco products are being proposed as an alternative mode of tobacco use associated with less harm. All of these products contain the tobacco-specific carcinogen N'-nitrosonornicotine (NNN). The major form of NNN in tobacco products is (S)-NNN, shown in this study to induce a total of 89 benign and malignant oral cavity tumors in a group of 20 male F-344 rats treated chronically with 14 p.p.m. in the drinking water. The opposite enantiomer (R)-NNN was weakly active, but synergistically enhanced the carcinogenicity of (S)-NNN. Thus, (S)-NNN is identified for the first time as a strong oral cavity carcinogen in smokeless tobacco products and should be significantly reduced or removed from these products without delay in order to prevent debilitating and deadly oral cavity cancer in people who use them.