We investigated whether long-term a-tocopherol therapy in chronic smoking affects superoxide generating capacity of neutrophilsex vivo. To this purpose, we randomly assigned 128 male chronic smokers (37 ± 21 pack years of smoking) to treatment with placebo(n = 64) or α-tocopherol (400 IU dL-α-tocopherol daily,n = 64). After two years of therapy, we measured phorbol 12-myristate 13-acetate-induced superoxide production of isolated neutrophils and of diluted whole blood by monitoring reduction of ferricytochrome c and luminol-enhanced peroxidase-catalyzed chemiluminescence. Plasma lipids and lipoproteins were not different between the two treatment groups. As expected, concentrations of a-tocopherol in plasma and in low-density lipoproteins were markedly elevated in the supplemented group compared to the placebo group (+ 120%,P 00001 and + 83%,P 00001, respectively). Consequently, resistance toin vitro oxidation of low-density lipoproteins (reflected by lag time of conjugated diene formation) was higher in the supplemented group than in the placebo group (+ 22%,P 00001). Superoxide generating capacity of neutrophils and superoxide production in diluted whole blood did not differ between α-tocopherol and placebo group. It is concluded that in chronic smoking long-term supranormal α-tocopherol intake does not reduce neutrophil superoxide-anion generating capacity, despite large increases in the concentrations of a-tocopherol in plasma and in low-density lipoproteins.