Large number of data showed that allele variants in certain genes are markers for hepatocellular carcinoma (HCC). GRP78 is a stress-associated protein which is a central regulator of endoplasmic reticulum homeostasis due to its multiple functional roles in the folding, maturation and transport of proteins. A case-control study was conducted on 576 HCC patients, and 539 age-and gender-matched healthy subjects to examine whether rs430397 polymorphism in the fifth intron of GRP78 gene is associated with the development and prognosis of HCC. Polymorphism in rs430397 was analyzed by resequencing and TaqMan real-time PCR. Allele A, genotype AA and combined genotypes (AG1AA) displayed significantly increased risk for HCC (OR 5 1.48, 95%CI 51.07-1.79, p50.010; OR 52.25, 95%CI5 1.08–3.38, p 5 0.019; and OR 5 1.50, 95%CI 5 1.09–1.85, p 5 0.012, respectively). Genotypes AA and AG were mainly associated with HBV-related HCC (85.8%; p<0.00001 versus HBV noncarriers with HCC) and cirrhosis-related HCC (90%; p50.011 versus noncirrhosis HCC). Patients carrying the AA genotype had a shorter survival time (median 23.0 months in all cases; median 21.0 months in the cases carrying HBsAg). Like HBV and cirrhosis, the rs430397 is an independent prognostic factor influencing the survival of HCC. In conclusion, allele A and genotypes AA and AG of rs430397 may represent high risk and poor prognosis for HCC.