Probucol (PBC) is a phenolic antioxidant that was once used as a lipid lowering agent. However, in addition to having moderate low density lipoprotein lowering ability, the drug is also found to significantly lower high density lipoprotein levels and cause QTc (corrected heart rate) prolongation. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that PBC has a much larger LUMO-HOMO energy difference than its major metabolite SPQ so that PBC would be more kinetically inert than SPQ. Whereas the molecular surface of PBC is found to possess significant amount of electron-rich (red and yellow) regions so that it can act as an antioxidant, that of SPQ is found to possess significant amount of electron-deficient (blue) regions so that it can react with cellular nucleophiles glutathione and nucleobases in DNA. Reaction with glutathione would induce cellular toxicity due to glutathione depletion whereas the oxidation of nucleobases would cause DNA damage.