We set out to study the effects of acute cigarette smoking on plasma antioxidants and lipid oxidation and whether these effects could be ameliorated by prior supplementation with ascorbate. Blood samples were taken from 9 apparently healthy male smokers before and after a 1 h smoking test (3 cigarettes/h). The men were then randomly allocated to two groups in a double-blind cross-over design; either taking ascorbate (100 mg/d) or placebo. After 2 wk of supplementation, the men were given a fat meal to consume and after 3 h the smoking test was repeated. Blood samples were taken before the fat tolerance test and at 3 and 4 h postprandially. In response to ascorbate supplementation, total plasma ascorbate increased relative to the placebo period (mean ± SEM: 70 ± 5 vs 46 ± 9 μmol/L, P = 0.01), with significantly less ( P = 0.025) ascorbate in the oxidized form (dehydroascorbate). Contrary to the depletion of antioxidants reported by others when plasma is exposed to cigarette smoke in vitro, no change was observed in plasma antioxidants in response to acute smoking, apart from a paradoxical decrease in the plasma concentration of dehydroascorbate after acute smoking (6.8 ± 1.1 vs 5.0 ± 1.1 μmol/L, P < 0.01). Plasma lipid peroxides (measured as thiobarbituric acid reactive substances) and copper-induced oxidizability of low-density lipoprotein showed no change after acute smoking. In response to a fat meal, plasma triglyceride concentrations peaked on average between 3 and 4h postprandially and LDL's content of lipid-soluble antioxidants (mostly α-tocopherol) decreased (8.1 ± 0.4 vs 7.4 ± 0.4 molecules/LDL particle, P = 0.023). This may render postprandial LDL more vulnerable to oxidation. The lack of effect of acute cigarette smoking on plasma antioxidant vitamins, apart from an apparent decrease in dehydroascorbate, suggests that compensatory mechanisms are at work in vivo with plasma ascorbate concentrations possibly replenished from other metabolic pools.