The mechanism by which dietary cis-unsaturated fatty acids lower low density lipoprotein (LDL) cholesterol is unknown. Because cis-unsaturated fatty acids incorporated into cell membranes increase membrane fluidity and, as a result, can alter membrane-dependent cell functions, we examined LDL binding, uptake, and degradation in upregulated U937 monocytes enriched in membrane oleate, a monounsaturated fatty acid, and membrane linoleate, a polyunsaturated fatty acid. The same parameters were also examined in upregulated U937 monocytes enriched in membrane stearate, a saturated fatty acid, and in upregulated, unmodified U937 monocytes. Monocytes enriched in cis-unsaturated fatty acids exhibited augmented LDL binding, internalization, and degradation compared with both stearate-enriched monocytes and unmodified monocytes. The molar potency of linoleate in augmenting LDL metabolism was 50% greater than that of oleate. Enrichment with oleate and linoleate resulted in a decrease in the fatty acyl mole-weighted melting point of the plasma membrane and an increase in plasma membrane fluidity, as indicated by a reduction in the steady-state fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene incorporated into the membrane. Stearate-enriched monocytes exhibited a slight increase in the plasma membrane fatty acyl mole-weighted melting point and essentially no change in plasma membrane fluidity. Thus, one mechanism by which cis-unsaturated fatty acids lower LDL cholesterol may involve alteration in membrane lipid composition and physical properties, thereby leading to an increase in cellular clearance of this atherogenic lipoprotein.