Apolipoprotein (apo) A-I(Milano) is an apo A-I mutant characterized by a cysteine for arginine substitution at position 173. Apo A-I(Milano) carriers have much less atherosclerosis than expected from their low plasma high-density lipoprotein cholesterol levels, suggesting that this mutant may have superior atheroprotective properties. Here, we compare the effect of hepatocyte-directed gene transfer of wild-type human apo A-I and human apo A-I(Milano) on endothelial progenitor cell (EPC) biology and on the progression of native atherosclerosis and allograft vasculopathy in C57BL/6 apo E(-/-) mice. Human apo A-I and apo A-I(Milano) transfer resulted in an equivalent increase of EPC number and function as well as EPC incorporation and endothelial regeneration in allografts and inhibited the progression of native atherosclerosis and allograft vasculopathy to a similar extent. In conclusion, the current head-to-head comparison indicates that human apo A-I(Milano) transfer is not superior compared to wild-type human apo A-I transfer.