Lipid peroxidation generates reactive aldehydes such as trans-4-hydroxy-2-nonenal and malonaldehyde, which form promutagenic exocyclic DNA adducts in human cells and may contribute to diet-related cancers. Using ultrasensitive detection methods, analysis of WBC DNA from volunteers in a dietary study revealed that high intake of omega-6 polyunsaturated fatty acids increased malonaldehyde-derived adducts in male and female subjects. In contrast, etheno adducts (1,N6-ethenodeoxyadenosine; 3,N4-ethenodeoxycytidine) were not elevated in males but were, on average, 40 times higher in females, displaying a huge intersubject variation in lipid peroxidation-derived DNA damage. Exocyclic DNA adducts are promising biomarkers for examining the hypothesis of possible links between increased intake of dietary omega-6 polyunsaturated fatty acids, DNA damage, and elevated cancer risk for breast, colon, and prostate.