Low molecule weight antioxidants such as uric acid (UA), glutathione (GSH), and ascorbate (ASC) counter the effects of oxidants produced by cigarette smoke. Although dietary intake of foods rich in antioxidants has been associated with a reduced risk of smokers developing chronic obstructive pulmonary disease (COPD), the association between plasma antioxidants and COPD is less clear. In this cross-sectional study we investigated the relationship among plasma antioxidants and COPD phenotypes (severity of airflow obstruction on spirometry and history of exacerbations) in 136 smokers with normal lung function and 367 smokers with COPD. In the multivariate analysis, a lower plasma UA was associated with more severe COPD (P < 0.002) and a lower GSH was associated with a history of COPD exacerbations (P = 0.03); ASC was not associated with any COPD phenotypes. This suggests that antioxidant balance is impaired in smokers with obstruction on spirometry or a history of COPD exacerbations.