We have previously shown that nitric oxide donors inhibit the oxidation of low density lipoprotein (LDL) initiated by copper ions or by azo-bis-amidinopropane (Hogg et al., 1993. FEBS Lett. 334: 170-174). In this study, the nitric oxide donors S-nitroso-N-acetylpenicillamine (SNAP), spermine NONOate, and sodium nitroprusside were tested for their ability to inhibit macrophage-dependent oxidation of LDL. SNAP and spermine NONOate inhibited macrophage-dependent oxidation of LDL in a time- and concentration-dependent manner. We propose that nitric oxide is acting as a chain-breaking antioxidant that can inhibit the progression of lipid peroxidation in cell dependent-oxidation of LDL. By this mechanism nitric oxide could be an endogenous defense against atherogenesis. In contrast, sodium nitroprusside enhanced cell-mediated oxidation of LDL by a mechanism dependent on superoxide production and transition metal ions. Sodium nitroprusside also enhanced LDL oxidation by cell culture medium alone by a similar mechanism. The use of sodium nitroprusside as a nitric oxide donor in cellular systems appears to be complicated by the release of iron leading to an enhanced oxidative stress. Thus the effects of sodium nitroprusside in such systems may be unrelated to nitric oxide release.