Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for the synthesis of most of the plasma cholesteryl esters, and plays a central role in intravascular HDL metabolism, in the determination of plasma HDL levels, and in macrophage cholesterol efflux and reverse cholesterol transport. Mutations in the human LCAT gene cause two LCAT deficiency syndromes, classical familial LCAT deficiency (FLD) and fish-eye disease (FED). Seventy-five mutations are listed in the Human Gene Mutation Database; 22 of these have been identified in Italian probands. The availability of a relatively large number of carriers of 2 and 1 mutant LCAT alleles allowed us to identify a significant LCAT gene-dose-dependent effect on plasma lipid and apolipoprotein levels, cholesterol esterification measurements, and HDL-related parameters. A highly significant LCAT gene-dose-dependent effect was found on carotid intima-media thickness, an established surrogate marker for human atherosclerosis, with homozygous (or compound heterozygous) carriers having less atherosclerosis than heterozygotes than controls. Therefore, LCAT deficiency is another monogenic HDL disorder leading to a paradoxical phenotype characterized by moderate to severe HDL deficiency without enhanced preclinical atherosclerosis. Moreover, despite the different functional defect of the LCAT enzyme in subjects carrying FLD and FED mutations, changes in HDL biomarkers and preclinical atherosclerosis are quite similar, suggesting that FLD and FED are not two distinct syndromes, but the same disease at different levels of LCAT impairment.