The reduced ratio of HDL-cholesterol over apoAI as induced by VLCD may be expected to result in an increased ability of total plasma and apoB-depleted plasma to induce cholesterol efflux from cholesterol-laden macrophages. However, we observed that the VLCD actually reduced the capacity of total plasma and apoB-depleted plasma to induce cholesterol efflux from THP-1 cells, even after discarding the three subjects showing the largest decrease in cholesterol efflux from the analysis. Correlation analysis revealed that HDL constituents (cholesterol, phospholipid, and apoAI) did not correlate with cholesterol efflux to plasma. Instead, the decrease in cholesterol efflux to plasma was mainly related to the decrease in total phospholipid levels in plasma. Collectively, these data indicate that the total lipoprotein surface area in plasma, rather than the HDL level, determines the capacity of plasma to induce cholesterol efflux.