Primary liver cancer is the third most common cause of cancer-related death worldwide, with a rising incidence in Western countries. Little is known about the genetic etiology of this disease. To identify genetic factors associated with hepatocellular carcinoma (HCC) and liver cirrhosis (LC), we conducted a comprehensive, genome-wide variation analysis in a population of unrelated Asian individuals. Copy number variation (CNV) and single nucleotide polymorphisms (SNPs) were assayed in peripheral blood with the high-density Affymetrix SNP6.0 microarray platform. We used a two-stage discovery and replication design to control for overfitting and to validate observed results. We identified a strong association with CNV at the T-cell receptor gamma and alpha loci (P < 1 × 10-15) in HCC cases when contrasted with controls. This variation appears to be somatic in origin, reflecting differences between T-cell receptor processing in lymphocytes from individuals with liver disease and healthy individuals that is not attributable to chronic hepatitis virus infection. Analysis of constitutional variation identified three susceptibility loci including the class II MHC complex, whose protein products present antigen to T-cell receptors and mediate immune surveillance. Statistical analysis of biologic networks identified variation in the "antigen presentation and processing" pathway as being highly significantly associated with HCC (P = 1 × 10-11). SNP analysis identified two variants whose allele frequencies differ significantly between HCC and LC. One of these (P = 1.74 × 10-12) lies in the PTEN homolog TPTE2. Conclusion: Combined analysis of CNV, individual SNPs, and pathways suggest that HCC susceptibility is mediated by germline factors affecting the immune response and differences in T-cell receptor processing.