Plasma phospholipid transfer protein (PLTP) enhances the generation of prebhigh density lipoproteins (HDL) that may act as initial acceptors of cellular cholesterol, and are likely to play an important role in the antiatherogenic process of reverse cholesterol transport. We examined the interrelationships between insulin resistance, the ability of plasma to stimulate cellular cholesterol efux, HDL cholesterol, plasma PLTP activity and preb-HDL in 12 nondiabetic, non-smoking, normotriglyceridaemic men. Cholesterol efux from Fu5AH cells to plasma, plasma lipoproteins, PLTP activity and preb-HDL formation as measured in incubated plasma were determined after a 12-h fast. Insulin sensitivity was assessed by a euglycaemic, hyperinsulinaemic clamp (M-value). HDL cholesterol was positively correlated with the M-value (r= 0.65, po 0.05), whereas plasma PLTP activity (r=±0.59, po 0.05) and preb-HDL in incubated plasma (r=±0.66, po 0.05) were negatively correlated with the M-value. Thus, the lower the insulin sensitivity, the lower was HDL cholesterol and the higher were plasma PLTP activity and preb-HDL. Cellular cholesterol ef ux tended to be correlated with HDL cholesterol (r= 0.55, po 0.10) as well as with plasma PLTP activity (r= 0.56, po 0.10) and was positively correlated with preb-HDL in incubated plasma (r= 0.74, po 0.01). No positive correlation between the M-value and cellular cholesterol ef ux was found (r=±0.34, ns). These preliminary results support the hypothesis that, despite a lower HDL cholesterol, the ability of plasma from insulin-resistant subjects to promote cellular cholesterol ef ux is not impaired, as a consequence of a higher plasma PLTP activity and enhanced preb-HDL formation.