Normal high density lipoprotein (N-HDL) is remodeled during acute phase (AP) reactions by the association of serum amyloid A (SAA) and the depletion of apolipoprotein (apo) A-I. To determine the impact of this remodeling on HDL function, the capacities of N-HDL and AP-HDL to associate with and promote cholesterol efflux from human monocytic THP-1 cells were compared. THP-1 cells preferentially bound AP-HDL compared with N-HDL. Examination of the AP-HDL particles bound to THP-1 cells revealed a disproportionate association of an apoSAA-enriched, apoA-I-depleted subpopulation compared with the composition of the starting material. However, N-HDL and AP-HDL promoted cholesterol efflux from THP-1 cells equally efficiently and in a dose-dependent manner. When N-HDL was experimentally remodeled with apoSAA to achieve an apoprotein composition similar to that of the preferentially bound particles, cellular cholesterol efflux was reduced by 30%. The remodelling of HDL with apoSAA during the acute phase reaction alters cholesterol efflux only when apoSAA constitutes more than 50% of the HDL protein.