Ezetimibe effectively reduces low-density lipoprotein cholesterol (LDL-C). In this study, we tested the hypothesis that ezetimibe monotherapy may also decrease markers of oxidative stress in subjects with hypercholesterolemia. Subjects with hypercholesterolemia and no evidence of cardiovascular disease were randomly allocated to open-label ezetimibe monotherapy 10 mg/day (EZT group) or therapeutic lifestyle changes (TLC group). At baseline and 12 weeks post-treatment serum lipoprotein and apolipoprotein levels as well as oxidative stress parameters, including oxidized LDL (ox-LDL), 8-isoprostanes (8-epiPGF2a) and reactive oxygen metabolites (d-ROMs) levels, were blindly determined. A total of 60 patients were included; 30 in each group. Despite a significant decrease in ox-LDL levels (by 20.8%, p < 0.001 vs. baseline; p < 0.001 vs. TLC group) in the EZT group no change in the ratio ox-LDL to LDL-C was noticed following ezetimibe treatment. No significant change in 8-epiPGF2a and d-ROMs levels was observed in the EZT group. Of note, a significant decrease in 8-epiPGF2a and d-ROMs levels (by 20.4% and 18.2%, respectively, p < 0.01 vs. baseline for both), was noted among patients in the EZT group who exhibited 'high oxidative stress' at baseline. No change in any of oxidative stress parameters was noted in the TLC group. Ezetimibe may decrease markers of oxidative stress in hypercholesterolemic subjects. This benefit may be more profound among patients who exhibit 'high oxidative stress' at baseline.