We studied the effect of variation at the lipoprotein lipase (LPL) gene locus on the susceptibility of individuals with Type 2 diabetes mellitus to atherosclerotic vascular disease in a population of 126 male and 114 female patients. The prevalence of any evidence of coronary heart disease (CHD) (presence of ischaemic ECG changes or definite myocardial infarction) was low in the patients who were homozygous for the presence of the PvuII restriction site (genotype 2-2) (40.9%) compared with those who were heterozygous (genotype 1-2) (57.9%; P = 0.05) or homozygous for the absence of it (genotype 1-1) (61.9%; P < 0.04). In men, a clear gene dosage effect on CHD was seen, the genotype 2-2 patients having the lowest (39.1%), the 1-2 patients an intermediate (49.3%) and the 1-1 patients the highest (61.1%) frequency of coronary disease. Patients with the genotype 2-2 of the HindIII polymorphism (absence of the restriction site) had the highest prevalence of any evidence of CHD (90.0%) compared with the genotype 1-2 (heterozygotes for the presence of the restriction site) (55.4%) or 1-1 (presence of the restriction site) (54.6%; P < 0.03). Stepwise discriminant analysis revealed that in the whole diabetic population the PvuII genotype of the LPL gene was independently and significantly associated with CHD but its effect decreased when the plasma lipids were taken into account. Overall, this study demonstrates the role of the PvuII polymorphism in the LPL gene to modulate the risk for diabetic macroangiopathy in patients with Type 2 diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)