Chronic inflammatory processes induce oxidative stress and lipid peroxidation (LPO), hereby generating DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE). Etheno-modified DNA bases are inter alia generated by reaction of DNA with HNE. Using an immunoaffinity-³²P-postlabeling method, the authors have investigated etheno-DNA adduct levels 1,N ⁶-ethenodeoxyadenosine (εdA) and of 3,N ⁴-ethenodeoxycytidine (εdC) in the pancreas of chronic pancreatitis patients and in the colon of patients with inflammatory bowel disease. Both εdA and εdC levels were found to be significantly, 3 and 28 times, respectively, elevated in the inflamed pancreatic tissue. In contrast, only εdC was found to be increased in affected colonic mucosa of Crohn’s disease (19 times) and of ulcerative colitis patients (4 times) when compared to asymptomatic tissues. In all three cancer-prone diseases, the mean εdC-levels in tissues were five- to ninefold higher than those of εdA. Differential or impaired DNA repair pathways of these adducts, known to occur by two different glycosylases are implicated. K-ras in pancreatic tumors and K-ras and p53 in colon mucosa in long-standing inflammatory bowel disease are known to be highly mutated. The conclusion is that promutagenic etheno-DNA adducts are generated as a consequence of chronic inflammation, acting as a driving force to malignancy in cancer-prone inflammatory diseases.