To test the hypothesis that variations in the multidrug resistance-1 gene influence the response to statin treatment, 2 prevalent polymorphisms (G2677T/A and C3435T) were examined in 344 hypercholesterolemic patients treated with atorvastatin (10 mg). The C3435T polymorphism was significantly and independently associated with a smaller reduction in low-density lipoprotein cholesterol and with a larger increase in high-density lipoprotein cholesterol, relative to variant allele carriers, in a gender-specific manner. Also, haplotype determination combined with these polymorphisms identified a subgroup that showed a striking response to treatment, which was not defined by a single polymorphism.