The role of apolipoprotein A-II (apoA-II) in the metabolism of high density lipoproteins (HDL) is poorly understood. Previous studies of naturally occurring variations of apoA-II in mice have, however, suggested that apoA-II expression influences HDL size and concentration. We now provide definitive evidence of this using transgenic mice overexpressing mouse apoA-II. Thus, as compared with nontransgenic littermates, transgenic mice possessing 4-fold elevations of apoA-II mRNA and 2-3-fold elevations in plasma apoA-II levels exhibited more than a 2-fold increase in HDL levels as well as about a 25% increase in average HDL diameter. Overexpression of mouse apoA-II also resulted in a substantial decrease in the levels of apolipoprotein E associated with HDL, suggesting that apoA-II can displace apoE from HDL. The apoA-II transgenic mice also exhibited a 2-4-fold increase in plasma very low density and low density lipoprotein-cholesterol levels, suggesting novel interactions among the classes of plasma lipoproteins.