Primary biliary cirrhosis (PBC) is an autoimmune liver disease, which affects approximately 1 in 1000 women over the age of 40. Many studies have supported the evidence that genetic predisposition has a critical role in the development of PBC. Identification of PBC susceptibility genes is the key to understanding its pathogenesis and improving its treatment. By using recent genome-wide association studies (GWAS), a number of loci have been identified as risk factors for the development of PBC. Among them, the major histocompatibility complex (MHC) harbors the PBC susceptibility region which exhibits the greatest effect size on the development of PBC. HLA-DRB*08:01 has been studied for many years and been known to confer the largest genetic effect. Recent GWA studies have also identified other PBC associated HLA alleles, including HLA-DQB*06:02, HLA-DQB*03:01 and HLADRB*04:04. However, the extensive linkage disequilibrium across the MHC region hampered the identification of potential independent risk loci. We used data from our previously reported GWAS, composed of 1840 PBC cases and 5175 geographically matched controls, as a discovery analysis set. Classical I and II HLA alleles were imputed by HLA*IMP. The analysis region was performed on all SNPs passing quality control within the extended MHC region, defined as the ~8Mb interval between SCGN and RPL12P1 (Build 37, chr6: 25 652 429-33 368 333). After the imputation of classical alleles and SNPs and the removal of redundant SNPs (r^2=1 with another SNP), the data set contained 56013 SNPs (of which 2239 had been experimentally genotyped) together with 83 variables representing the class I and II HLA alleles. Another previously reported GWAS composed of 453 PBC cases and 936 geographically matched controls, as a replication analysis set. Conditional and stepwise logistic regression was performed using the ‘condition' function in PLINK to determine whether independent effects existed. Briefly, starting with HLA-DRB*08:01, HLADQB*06:02, HLA-DQB*03:01 and HLA-DRB*04:04, which have be reproducibly associated with PBC, we conditioned candidate HLA alleles on these four HLA alleles to determine the next most significant independent effect. we observed and replicated two additional independent signals for disease association. We detected evidence for association at SNPs rs3135024 (5.75E-27) and rs116518618 (1.93E-08), located within the class III region of the MHC, with each observation replicated in an independent sample (P ≤ 0.05).