The purpose of this study was to determine whether vitamin E or vitamin C supplementation alters the DNA damage of whole blood white blood cells (WBC) in patients with chronic obstructive pulmonary disease (COPD). Thirty-five patients with stable COPD were recruited in this randomized and placebo-controlled study. Patients were randomly assigned to placebo (n = 8), 400 mg/day vitamin E (E400, n = 9), 200 mg/day vitamin E (E200, n = 9), or 250 mg/day vitamin C (C250, n = 9) for 12 weeks. The results showed that vitamin E or C supplementation did not significantly change the mean level of endogenous DNA breakages. Whereas, after 12 weeks of vitamin supplementation, the H2O2-induced DNA breakages were significantly suppressed by 45%, 59%, and 52%, respectively, in E400, E250 and C250 groups (p < 0.05). In addition, neither the level of thiobarbituric acid-reactive substances (TBARS) nor spirometric parameters were significantly changed after 12 weeks of supplementation. In conclusion, vitamin E or C supplementation for 12 weeks may improve the resistance of DNA in whole blood WBC against oxidative challenge, although more research is needed to demonstrate the beneficial effect on slowing the decline of lung function in patients with COPD.