The aim of the present study was to examine the effect of variation at the apolipoprotein (apo) A-II gene locus on lipoprotein levels in visceral obesity. A total of 145 sedentary men, free from metabolic disorders requiring pharmacotherapy, were classified into two groups on the basis of their apo A-II-MspI genotype determined by the polymerase chain reaction: 1) 43 M1 carriers or M1M2, including two M1M1 homozygotes and 41 M1M2 heterozygotes, and 2) 102 M2M2 homozygotes for the presence of a MspI restriction site. The two genotypic groups did not differ for body mass index (BMI, expressed in kg/m2), body fat mass, visceral adipose tissue (AT) accumulation, as well as for insulin, glucose and free fatty acids levels measured in the fasting state and in response to an oral glucose tolerance test. In addition, 65 and 63% of M1 carriers had plasma HDL2 cholesterol levels and a HDL2/HDL3 cholesterol ratio below the 50th percentile of their distributions compared with 45%(P < 0.05) and 46%(P = 0.06), respectively, in M2M2 homozygotes. When subjects were further divided on the basis of visceral AT accumulation (below and above a value of 130 cm2), M1 carriers with low levels of visceral AT were characterized by high plasma HDL cholesterol and HDL2 cholesterol concentrations as well as by a higher HDL2/HDL3 ratio, compared with M1 carriers with high levels of visceral AT (> 130 cm2), or with M2M2 homozygotes with either a high or a low accumulation of visceral AT. Furthermore, M1 carriers with high levels of visceral AT showed a trend for lower plasma HDL2 cholesterol levels and were characterized by a significantly lower HDL2/HDL3 cholesterol ratio compared with the other three groups. No difference in HDL and HDL2 cholesterol levels and in the HDL2/HDL3 cholesterol ratio was noted when M2 homozygotes with lower versus higher levels of visceral AT were compared. The contribution of hyperinsulinemia was also examined by dividing subjects on the basis of the 50th percentile of the integrated insulin response to an oral glucose challenge. Significantly lower plasma HDL2 cholesterol levels and a reduced HDL2/HDL3 cholesterol ratio were noted among M1 carriers with high plasma insulin responses compared with M1 carriers with low insulin responses. Among M2M2 homozygotes, no difference was noted in plasma HDL cholesterol and in HDL2 cholesterol concentrations between men with low versus high insulin responses to the oral glucose load. These results suggest that the apo A-II-MspI polymorphism could modulate plasma HDL cholesterol levels among visceral obese, insulin-resistant men.