The addition of bacterial lipopolysaccharide (LPS) from Escherichia coli 0111:B4 or Salmonella minnesota R595 to plasma (or serum) resulted in a marked reduction of the hydrated buoyant density of the parent LPS (0111:B4 [d = 1.44 g/cm3] and R595 [d = 1.38 g/cm3]), to d less than 1.2 g/cm3. This reduction in buoyant density to less than 1.2 g/cm3 of the LPS required plasma (or serum) lipid. Delipidation of plasma (or serum) by extraction with n-butanol/diisopropyl ether (40/60, vol:vol) prevented the conversion of the parent LPS to a form with d less than 1.2 g/cm3. Reversal of the effect of delipidation was accomplished by the addition of physiologic concentrations of high density lipoprotein (HDL). In contrast, as much as two times normal serum concentration of low density or very low density lipoprotein were ineffective. The ability of normal plasma (or serum) to inhibit the pyrogenic activity of LPS, lost after delipidation, was also restored after the addition of HDL. Preliminary results suggested that prior modifications of the LPS, probably disaggregation, may be required before interaction with HDL.