The aim of the present study was to examine the impact of the defective D9N and the null P207L mutations in the lipoprotein lipase (LPL) gene on high density lipoprotein (HDL) particle size in relation to specific environmental factors such as obesity, gender and menopausal status. Analyses were carried out in 118 heterozygous carriers of the D9N mutation and 88 heterozygous for the P207L mutation. HDL particle size was measured on whole plasma by non-denaturing 4-30% polyacrylamide gradient gel electrophoresis. Although carriers of the P207L mutation presented a more deteriorated lipoprotein-lipid profile compared with carriers of the D9N mutation, there was no difference in HDL particle size between the P207L and D9N carriers (81.9+/-4.5 vs. 82.7+/-4.4 A, respectively, P=0.2). Multivariate analyses indicated that waist circumference (P=0.001) and HDL cholesterol levels (P<0.001) were independent predictors of HDL particle size among carriers of the defective D9N mutation. On the other hand, gender (P=0.03), plasma cholesterol (P=0.01) and TG (P=0.04) levels were significant predictors of HDL particle size among carriers of the null P207L mutation in multivariate analyses. These results suggest that the nature of the mutation in the LPL gene modifies the relationship of HDL particle size to other metabolic variables and secondary factors such as abdominal obesity and gender.