In vitro exposure of fresh human plasma to cigarette smoke (CS) was used as a model for reactions that could be occurring in CS-exposed respiratory tract lining fluids (RTLFs) and lung parenchyma. The central focus of this model was to characterize the consumption of endogenous plasma antioxidants in relationship to the appearance of oxidized proteins and lipids as a consequence of exposure to CS, or to aldehydes present in CS. The amelioration of CS-induced protein and lipid oxidation in plasma by the addition of selective exogenous antioxidants was also assessed. We found that: (i) exposure of human plasma to gas phase CS causes both lipid peroxidation and protein oxidation, and endogenous ascorbic acid protects against lipid, but not protein, oxidation; (ii) whole CS causes protein oxidation, but does not induce lipid peroxidation; (iii) addition to plasma of aldehydes known to be present in CS causes protein damage, but does not induce either lipid peroxidation or oxidation of ascorbic acid; and (iv) exogenously added dihydrolipoic acid (DHLA) preserves ascorbic acid levels in plasma exposed to the gas phase of CS, and protects, to some extent, against lipid peroxidation; DHLA also protects against protein oxidation, whereas added glutathione (GSH) only protects against protein, but not lipid, oxidation.