Nicotine is a naturally occurring alkaloid found primarily in members of the solanaceous plant family, which includes tobacco. Nicotine is rapidly absorbed by humans and then metabolized, primarily by cytochrome P450's. Studies on the genotoxic potential of these metabolites are limited. Nicotine and four of its major metabolites: cotinine, nicotine-N'-oxide, cotinine-N-oxide, and trans-3'-hydroxycotinine were evaluated for genotoxic potential in the Salmonella mutagenicity assay (strains TA98, TA100, TA1535, TA1537, and TA1538) at concentrations ranging from 0 to 1000 micrograms/plate and in the Chinese hamster ovary sister-chromatid exchange (SCE) assay at concentrations ranging from 0 to 1000 micrograms/ml. All assays were conducted with and without S9 metabolic activation. None of the five compounds increased the frequency of mutations or the frequency of SCEs. These results indicate that nicotine and its major metabolites are not genotoxic in the assays conducted.