The potential of phenobarbital to interact with DNA has been studied using the sister chromatid exchange (SCE) assay in peripheral lymphocytes of nine adult male patients with epilepsy and of their matched controls. All patients were otherwise healthy individuals, treated chronically with phenobarbital in monotherapy. No statistically significant differences in SCE levels were found between the patient and control groups. Smoking was associated with increased SCE frequencies. The experiment was repeated with five available patients, using a slightly modified methodology. Although different SCE scores were obtained, the results of both tests were comparable.