1. Ca2+ channel blockers from 3 different chemical classes (diltiazem, verapamil and nifedipine) were compared in their ability to inhibit low density lipoprotein (LDL) oxidation and to protect cells directly against the cytotoxicity of oxidized LDL. 2. LDL oxidation promoted either by u.v. radiations or by copper ions was inhibited by nifedipine (IC50 of 10 +/- 2 and 4 +/- 0.5 mumol l-1, respectively) whereas diltiazem and verapamil were only poorly active or completely ineffective. As expected, LDL protected from oxidation by nifedipine (nifedipine/oxidized LDL) were much less cytotoxic than (unprotected) oxidized LDL (or than LDL oxidized in the presence of diltiazem or verapamil). The cytotoxic effect correlated well with the lipid peroxidation derivatives measured as the thiobarbituric acid reactive substances (TBARS) content of LDL oxidized in the presence of Ca2+ channel blockers, which suggests that the antioxidant effect of Ca2+ channel blockers protected cells indirectly from the cytotoxic effect of oxidized LDL. 3. Nifedipine also exhibited a direct cytoprotective effect against the cytotoxicity of oxidized LDL as demonstrated by incubating cells in the presence of unprotected oxidized LDL and nifedipine (IC50 of 1 +/- 0.2 mumol l-1), whereas diltiazem and verapamil did not exhibit any significant protective effect. At the concentrations used, the protective effect of nifedipine was not due to inhibition of LDL uptake by Ca2+ channel blockers. 4. The direct protective activity of nifedipine is probably unrelated to its antioxidant properties since it did not inhibit the cellular TBARS evoked by oxidized LDL taken up by the cells, in contrast to vitamin E. 5. Nifedipine (and diltiazem to a lesser extent) inhibited the slow [Ca2+]J rise induced by oxidized LDL and the subsequent cytotoxicity.6. It is proposed that relatively high concentrations of nifedipine (unlike diltiazem and verapamil)protect cultured lymphoid cells against the cytotoxicity of oxidized LDL by two different mechanisms:(i) an antioxidant effect inhibiting LDL oxidation (outside the cell); (ii) a direct cytoprotective effect (at lower concentrations), the mechanism of which is unknown. These data could explain in part the mechanism of action of nifedipine in the prevention of cellular damage potentially involved in atherogenesis.