Oxidative damage has been implicated in the pathogenesis of inflammatory bowel diseases. 5-Aminosalicylic acid (5-ASA), the anti-inflammatory drug commonly used in the treatment of this condition, has been shown to possess antioxidant properties considered to be of particular importance in the pathologic context of these diseases. However, its action mechanisms are far from being completely elucidated, especially regarding its antioxidant properties in the presence of endogenous antioxidants such as α-tocopherol (α-T), the major defence system of biomembranes against lipid peroxidation. In this study we investigated the scavenging activity of 5-ASA toward peroxyl radicals generated at different sites of soybean PC liposomes, used as model membranes, either alone or in combination with α-T. 5-ASA, separately, shows strong scavenging activity toward peroxyl radicals generated in the aqueous phase by thermal decomposition of 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH), inducing a clear concentration-dependent inhibition period, either of oxygen consumption or of conjugated diene hydroperoxides production. HPLC analysis indicates that 5-ASA is consumed, at a constant rate, throughout the reaction, and when the inhibition period is over, the oxidation rate is resumed. On the other hand, apart from a slight decrease in the rate of oxidation, 5-ASA is unable to suppress efficiently lipid peroxidation, when the reaction starts inside the lipid membranes, by thermal decomposition of 2,2′-azobis(2,4-dimethylvaleronitrile) (AMVN).When 5-ASA is combined with α-T, and the oxidation starts in the aqueous phase, an additive inhibitory effect occurs between both compounds. 5-ASA protects efficiently α-T against initial attack from AAPH-peroxyl radicals, delaying its consumption. On the other hand, if the reaction starts inside the lipid bilayer, 5-ASA prolongs significantly the inhibitory period produced by α-T on the initial rate of oxidation, as measured by oxygen consumption and conjugated diene hydroperoxides. This inhibitory effect points to a synergistic interaction between 5-ASA and α-T, since 5-ASA, by itself, is unable to suppress the oxidation reaction. Therefore, 5-ASA reveals an important cooperative effect with α-T, either affording an efficient protection to this antioxidant compound, when free radicals are generated in the aqueous site, or potentiating its activity when oxidation is initiated inside the lipid bilayer. Taking into account that the ascorbic acid content decreases significantly in the inflamed mucosa of patients with inflammatory bowel diseases, our data are, certainly, a very important contribution to the knowledge of the anti-inflammatory action of 5-ASA.