The precise mechanism by which unsaturated fatty acids lower low density lipoprotein cholesterol is not known. Because cis-unsaturated fatty acids incorporated in cell membranes increase membrane fluidity and can thereby dramatically alter membrane-dependent cellular functions, we examined the effect of linoleate and oleate incorporation in peripheral blood mononuclear cell membranes on the physical properties of the membrane and concomitantly on low density lipoprotein uptake and degradation. We found that membrane enrichment with linoleate increased the rate of low density lipoprotein degradation in both freshly isolated and derepressed mononuclear cells. Enrichment with oleate led to similar increases in degradation. "Specific" low density lipoprotein uptake by derepressed cells was also enhanced by linoleate and oleate incorporation. Enrichment with both of these fatty acids produced an increase in membrane fluidity, as indicated by a reduction in the steady-state fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene incorporated in the membrane. In contrast, stearate enrichment had little effect on uptake or degradation of low density lipoprotein, nor did it affect membrane fluidity. These data point to a novel mechanism for the reduction in low density lipoprotein produced by unsaturated fatty acids that involves their physical effects on cell membranes as it relates to metabolism of the lipoprotein.