The objective of this study was to evaluate the influence of c.1564A>T genetic polymorphisms in the multidrug resistance 1 gene (MDR1) on hepatocellular carcinoma (HCC) susceptibility through association analysis. A total of 632 HCC patients and 645 cancer-free controls were enrolled in this study. The c.1564A>T genetic polymorphisms were genotyped by created restriction site-polymerase chain reaction (CRS-PCR) and confirmed using DNA sequencing methods. The potential associations of c.1564A>T genetic polymorphisms with the risk of HCC were analyzed by different genetic models. Statistically significantly increased risks of HCC were detected in the homozygote comparison (TT versus AA: OR = 1.70, 95%CI = 1.17-2.45, χ(2) = 7.99, P = 0.005), recessive model (TT versus
At/aa: OR = 1.64, 95%CI = 1.15-2.33, χ(2) = 7.66, P = 0.006), and allele contrast (T versus A: OR = 1.23, 95%CI = 1.04-1.45, χ(2) = 6.09, P = 0.014). Our data suggest that the genotypes/alleles from c.1564A>T genetic polymorphisms are statistically associated with HCC risk. The allele-T and genotype TT may contribute to susceptibility to HCC in the Chinese Han population.