The potential of the widely prescribed antiepileptic drugs (AEDs) phenytoin (PHT) and phenobarbital (PB) to interact with genetic material was tested using sister chromatid exchange (SCE) assay. Thirty adult male patients with epilepsy receiving long-term AED therapy (16 with PHT, 6 with PB, and 8 with combined PHT and PB therapy) and 30 healthy controls were selected for the study of SCE frequencies in peripheral lymphocytes. The patients and controls were carefully screened and matched for sex, age, and smoking habits. All potential probands with exposure to factors known or suspected of affecting the SCE frequencies were excluded. Statistical analyses did not show any significant differences between the SCE rates of PHT- and/or PB-treated patients and controls, indicating a lack of mutagenicity of the tested drugs as expressed by induction of SCE on adult recipients. Smoking, however, affected the SCE levels considerably. The smokers had higher SCE frequencies than the nonsmokers, both among patients and controls. Caffeine consumption was also associated with SCE increases in patients but not in controls.