In the present study, the possible role of the polyunsaturated fatty acids linoleic and arachidonic acid in the chemical induction of carcinogenesis has been investigated. Analysis of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) levels in 2'-deoxyguanosine (dG) and isolated DNA has demonstrated that linoleic and arachidonic acid are capable of inducing this specific genotoxic damage. This effect appears to be related to the degree of fatty acid unsaturation, since it was not induced by monounsaturated oleic acid. Enzymatic peroxidation of linoleic and arachidonic acid resulted in a significant increase in oxidative DNA damage. Studies on the interference of radical scavengers with the induction of 8-oxodG in combination with electron spin resonance spectroscopy demonstrated that the superoxide anion was generated during peroxidation of these fatty acids and that singlet oxygen is most likely involved in the formation of oxidative DNA damage. The level of oxidative damage in dG and single-stranded DNA was higher as compared to that in native DNA after equimolar treatment. Exposure of human lymphocytes to linoleic or arachidonic acid did not result in a significant increase in levels of 8-oxodG. This may indicate that the rate of intracellular peroxidation is relatively low and/or that nuclear DNA in intact cells is effectively protected against genetic damage induced by reactive oxygen species. It is therefore concluded that relatively short periods of linoleic or arachidonic acid administration are not likely to impose a direct genotoxic risk. It can, however, not be excluded that chronic exposure to polyunsaturated fatty acids induces oxidative DNA damage or is related to cancer risk by epigenetic mechanisms, as is also indicated by the observed cytotoxic effects of linoleic and arachidonic acid.