The human multidrug resistance gene 1 (MDR-1) encodes a plasma membrane P-glycoprotein (P-gp) that functions as the transmembrane efflux pump for various structurally unrelated anticancer agents and toxins. Polymorphisms in the MDR-1 gene may have an impact on the expression and function of P-gp, thereby influencing the susceptibility to various diseases, including cancer. We investigated the incidence of C3435T polymorphisms at exon 26 in the MDR-1 gene in 92 women with breast cancer and potential association of altered genotypes with smoking and high body mass index in cancer development among patients. The MDR-1C3435T allelotype and genotype analysis revealed a high incidence (75.0%) of polymorph alteration in the MDR-1 gene. The frequencies of homozygous T/T, heterozygous C/T and homozygous C/C genotypes were 25.0, 50.0 and 25.0%, respectively. The risk of breast carcinoma in patients with MDR-1 polymorphism was significantly associated with the higher body mass index, where women with BMI >30 kg/m(2) and C allele in genotype had a higher risk of disease compared to patients with lower amounts of body fat tissue (p=0.0439). The risk was highest for the homozygous carriers of C allele with BMI >30 kg/m(2) compared to patients with BMI 25.1-30 or <or=25 kg/m(2) (OR 3.65, 95% CI 0.94-14.20; or OR 2.50, 95% CI 0.55-11.41), respectively. Consistent with the results of genotyping and BMI analyses, smoking patients harboring the C/T or C/C genotype had an increased risk of cancer (OR 1.28, 95% CI 0.23-7.17; OR 1.58, 95% CI 0.28-10.44, respectively) when exposed to carcinogens in tobacco smoke, although it was not statistically significant. Our findings suggest that the MDR-1C3435T polymorphism occurs in high incidence among women with breast carcinoma where C allele carriers have increased risk of developing cancer when exposed to toxic substances. Our observations are the first that indicate this polymorphism as a modulator of health to be associated with an increased risk of breast cancer.