A series of structurally related dibenzo[1,4]dichalcogenines possessing similar lipid solubilities but greatly differing oxidation potentials were tested for their ability to inhibit stimulated lipid peroxidation in ADP/Fe2+/ascorbate-treated liver microsomes and in hepatocytes treated with either t-butylhydroperoxide or diquat. In general, there was a close correlation between the half-wave oxidation potential of a particular compound and its antioxidant activity in the microsome and cell systems, with compounds possessing the lowest potential being the most potent antioxidants and vice versa. The Te/O and Te/S and S/O-substituted compounds, with oxidation potentials between 0.65 and 0.87 V, demonstrated most potent activity. Above this potential the antioxidant activity of the structure declined rapidly. The Te/O and Te/S compounds are among the most potent synthetic antioxidants described possessing IC50 values in the microsome system lower than 0.5 microM. This study clarifies the critical role of redox potential of an antioxidant site on a particular molecule without the complication of variable lipid solubility and may allow the definition of an optimal potential for antioxidant activity in biological systems.