Genetic predisposition of nuclear factor-kappa B (NF-kappaB)-signaling pathways linking inflammation to hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remains unresolved. We conducted a case-control study to determine the associations of the polymorphisms within the promoter regions of NFKB1 encoding NF-kappaB1 and NFKBIA encoding IkappaBalpha with the development of HCC. A total of 404 healthy controls, 482 non-HCC subjects with HBV infection and 202 patients with HCC were included. NFKB1 -94ATTG2 allele and GG allele in the 3'-untranslated region of NFKBIA were more prevalent in HCC patients than in the healthy controls. NFKBIA -826CT and NFKBIA -881AG allelic carriages were more prevalent in HCC patients than in the non-HCC subjects with HBV infection. The estimated haplotype frequency of NFKBIA promoter -881G-826T-519C was significantly higher in the patients with HCC than in the HBV-infected subjects without HCC (odds ratio = 3.142, P = 0.002). As compared with the HBV-infected subjects without HCC, NFKBIA -826 T and NFKBIA -881AG allelic carriages were only associated with HCC risk in the subjects with HBV genotype C. The association of NFKBIA -881AG allelic carriage with HCC risk was not affected by liver cirrhosis (LC) status, alanine aminotransferase level and hepatitis B e antigen status. By multivariate regression analysis, NFKB1 -94ATTG2, NFKBIA -826T, NFKBIA -881AG and HBV genotype C were independently associated with an increased risk of HCC. In conclusion, NFKB1 -94ATTG2 allele and haplotype -881G-826T-519C in NFKBIA promoter were associated with hepatocarcinogenesis. NFKBIA -826T and -881AG were associated with the risk of HCC in the subjects infected with HBV genotype C.