To gain further insights into the relationship between plasma phospholipid transfer protein (PLTP) and lipoprotein particles, PLTP mass and phospholipid transfer activity were measured, and their associations with the level and size of lipoprotein particles examined in 39 healthy adult subjects. No bivariate correlation was observed between PLTP activity and mass. PLTP activity was positively associated with cholesterol, triglyceride, apo B and VLDL particle level (r(s)=0.40-0.56, p< or =0.01) while PLTP mass was positively associated with HDL-C, large HDL particles, and mean LDL and HDL particle sizes (r(s)=0.44-0.52, p<0.01). Importantly, plasma PLTP specific activity (SA) was significantly associated with specific lipoprotein classes, positively with VLDL, IDL, and small LDL particles (r(s)=0.42-0.62, p< or =0.01) and inversely with large LDL, large HDL, and mean LDL and HDL particle size (r(s)=-0.42 to -0.70, p< or =0.01). After controlling for triglyceride levels, the correlation between PLTP mass or SA and HDL size remained significant. In linear models, HDL size explained 45% of the variability of plasma PLTP SA while triglyceride explained 34% of the PLTP activity. Thus, in healthy adults a significant relationship exists between HDL size and plasma PLTP SA (r(s)=-0.70), implying that HDL particle size may modulate PLTP SA in the vascular compartment.