High density lipoproteins (HDL) in human cord blood have previously been shown to exhibit particle size profiles distinctly different from those of adult HDL. The adult HDL profile is comprised of separate contributions from two major apolipoprotein-specific populations; one population contains both apolipoproteins AI and AII (HDL(AIwAII], while the other has apolipoprotein AI without AII (HDL(AIw/oAII]. The present studies establish that cord blood HDL are also comprised of HDL(AIwAII) and HDL(AIw/oAII) populations whose particle size profiles closely reflect cholesterol and HDL-cholesterol levels in cord blood. Compared with the adult, cord blood HDL(AIwAII) profiles generally show both a greater subspeciation within HDL2a and HDL3b/3c size intervals as well as relative reduction of material in the HDL3a interval. In the cord blood HDL(AIw/oAII) profile, HDL2b(AIw/oAII) particles also show subspeciation with a major component that is consistently larger than that normally observed in the adult (11.2 vs. 10.3 nm). As in the adult, the HDL3a(AIw/oAII) component is present but, unlike the adult, its relative amount is low; hence, its peak is usually not discernable in the cord blood total HDL profile. Our studies show that the larger-sized HDL2b(AIw/oAII) of cord blood are enriched in phospholipid which probably accounts for their increased size. The protein moiety of the larger-sized HDL2b(AIw/oAII) has a molecular weight equivalent to four apolipoprotein AI molecules per particle similar to the normal-sized adult subpopulation. Phospholipid enrichment of cord blood HDL(AIwAII) subpopulations within the HDL2a size interval was not observed. However, the protein moiety of cord blood HDL2a(AIwAII) is unusual in that it exhibits an apolipoprotein AI:AII molar ratio considerably lower (0.8:1 vs. 1.6:1) than that of adult. We suggest that the unique particle size distribution of cord blood total HDL is due in large part to: (a) a specific enrichment of phospholipid in HDL2b(AIw/oAII) species, producing particles larger than normal adult counterparts and (b) an elevated proportion of apoAII carried by the HDL(AIwAII) particles that may influence subspeciation in the HDL3a/b/c size interval.