Fatty acid ethanolamides (NAEs) are naturally occurring hydrophobic molecules usually present in a very small amount in many mammalian tissues and cells. Moreover, these compounds have been isolated in mammalian biological fluids, such as blood. Palmitoylethanolamide (C16:0) (PEA) is a fully saturated NAE, which presents some possible pharmaceutical activities, such as anti-inflammatory and antinociceptive effects. PEA is physiologically present in the mammalian blood at concentrations ranging from 9.4 to 16.7 pmol/ml. Since increasing evidence indicates that oxidative modification of low-density lipoproteins (LDL) is an important determinant in atherogenesis, the aim of this study was to evaluate the effect of physiologically relevant concentrations of PEA on Cu2+-induced LDL oxidation (measured as conjugated dienes formation). Our experiments indicate both anti-oxidative and slightly pro-oxidative effects of PEA. The anti-oxidative effect is obtained at low PEA concentrations (0.01 and 0.1 microM), while the pro-oxidative effect is obtained at a higher PEA concentration (1 microM). Fluorescence and circular dichroism data indicate that the effect of PEA occurs mainly by affecting the conformational features of ApoB-100.