Familial hypercholesterolaemia (FH) is an autosomal dominant disease characterized by elevated levels of low-density lipoprotein-cholesterol (LDL-C). Phenotypic expression is highly variable, being influenced by diet, age, gender, body mass index, apolipoprotein E genotype and type of LDL-receptor gene mutation. Microsomal triglyceride (TG) transfer protein (MTP) is a protein involved in lipid metabolism. Polymorphism MTP -493 GT has been shown to modulate lipid levels in several populations. To analyse the effect of this polymorphism in the lipid phenotype expression of FH and treatment response, we studied a sample of 222 Spanish FH patients, of whom 147 were studied before and after treatment with 20 mg of atorvastatin daily during 6 weeks. The variant was analysed by polymerase chain reaction amplification and single-strand confirmation polymorphism. Treatment reduced LDL-C, total cholesterol and TGs. Baseline fasting TGs and very-low-density lipoprotein cholesterol levels were lower in female T allele carriers (TG: 111+/-51 mg/dl GG, 89+/-35 mg/dl GT, 83+/-26 mg/dl TT, P=0.022; very-low-density lipoprotein cholesterol: 24+/-13 mg/dl GG, 16+/-5 mg/dl GT, 17+/-5 mg/dl TT, P=0.018). Triglyceride response to atorvastatin was modulated by this polymorphism in men (P=0.009), but not in women, although differences between genotypes were maintained after treatment. In conclusion, the MTP -493 GT polymorphism modulates pre- and post-treatment plasma TG values of FH in Spanish subjects in a gender-specific way. Other environmental and genetic factors likely also modulate this response.