Extra-virgin olive oils (EVOO), high in phenolic compounds with antioxidant properties, could be partly responsible for the lower mortality and incidence of cancer and CVD in the Mediterranean region. The present study aims to measure oxidative DNA damage in healthy human subjects consuming olive oils with different concentrations of natural phenols. A randomised cross-over trial of high-phenol EVOO (high-EVOO; 592mg total phenols/kg) V low-phenol EVOO (low-EVOO; 147mg/kg) was conducted in ten postmenopausal women in Florence. Subjects were asked to substitute all types of fat and oils habitually consumed with the study oil (50g/d) for 8 weeks in each period. Oxidative DNA damage was measured by the comet assay in peripheral blood lymphocytes, collected at each visit during the study period. Urine samples over 24h were collected to measure the excretion of the olive oil phenols. The average of the four measurements of oxidative DNA damage during treatment with high-EVOO was 30% lower than the average during the low-EVOO treatment (p=0·02). Urinary excretion of hydroxytyrosol and its metabolite homovanillyl alcohol were significantly increased in subjects consuming high-EVOO. Despite the small sample size, the present study showed a reduction of DNA damage by consumption of an EVOO rich in phenols, particularly hydroxytyrosol.