Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs). We previously showed that 3'-end haplotypes in the LPL gene influence atherosclerosis and insulin resistance. This study asked whether these LPL haplotypes influence response to lipid-lowering therapy among 829 subjects from the Post-Coronary Artery Bypass Graft trial. Lipid profiles were obtained at baseline and 4-5 years after treatment with lovastatin. Haplotypes were based on 12 SNPs. The fourth most frequent haplotype, 12-4, was associated with a decreased increment in high-density lipoprotein-cholesterol (HDL-C) following treatment. Haplotypes 12-6, 12-7 and 12-8 were each associated with increased HDL-C response to therapy, and haplotype 12-2 with decreased TG response. The most common haplotype, 12-1, was protective against graft worsening or occlusion. Haplotype 12-4 reduced HDL-C response to lovastatin, possibly consistent with our prior observations of this haplotype as predisposing to coronary artery disease. LPL may influence atherosclerosis risk through pleiotropic effects on each aspect of the metabolic syndrome.