The aim of this study was to investigate the possibility of a significant relationship between human leukocyte antigen (HLA) class II and the clearance of hepatitis C virus (HCV). The study group consisted of 156 Irish women who iatrogenically received HCV 1b–contaminated Anti-D immunoglobulin between May 1977 and November 1978. Thus, the study population was homogeneous in terms of gender, source of infection, and ethnicity. On Screening in 1994, all individuals were anti-HCV antibody positive by recombinant immunoblot assay, while 46% (n = 72) of the group were HCV-positive by reverse transcriptase-polymerase chain reaction (RT-PCR). HLA DRB1 and DQB1 status was molecularly defined by high resolution reverse line probe hybridization methodology. Clearance of HCV 1b was found to be associated with DRB1*01. However, this association was lost after Bonferroni correction for multiple comparisons. Extended haplotype analysis between specific DRB1 and DQB1 allelic combinations identified a significant reduction in the frequency of DQB1*0501 in the presence of DRB1*0701 in the persistently infected individuals in the study group (P < .05). No associations with either viral clearance or persistence were found at the DQB1 locus. Our results suggest that HLA DRB1*01 appears to contribute to the spontaneous resolution of a primary HCV infection in the Irish population. The presence of DRB1*0701 in the absence of DQB1*0501 possibly reflects an influence of this allele in persistence of HCV infection. Defined and homogeneous patient populations offer the best opportunity to illuminate previously disguised immunogenetic factors important in the clearance of HCV 1b.