Paraoxonase (PON), an HDL- associated enzyme, may protect against the development of atherosclerosis. Single nucleotide polymorphisms of PON have been reported to be associated with an incidence of coronary heart diseases. We investigated the effect of PON R192Q variants on serum lipid profile after caloric restriction in nondiabetic healthy males. After caloric restriction for 12 weeks, the levels of high-density lipoprotein cholesterol (HDL-C) increased in the subjects carrying RR genotype, but not in the QR and QQ genotypes. The changes in HDL-C from the baseline values in the RR genotype were significantly different from those in the QR and QQ genotypes. Although the changes in lipoprotein lipase activity were not different among three genotypes, we observed a significant difference in the changes in hepatic lipase (HL) activity after caloric restriction, namely, a decrease in the RR genotype and an increase in the subjects carrying the Q allele. In addition, the changes in fasting insulin levels significantly correlated with those in HDL-C levels in the RR genotype, not in the QR and QQ genotypes. PON R192Q polymorphism could affect HDL-C levels after caloric restriction presumably due to decreased HL activity and altered insulin resistance.