The association of human leukocyte antigen (HLA) genes with the outcome of hepatitis C virus (HCV) infection may be modified by ethnic and geographical differences.HLA-A, -C, -DRB1 and -DQB1 genotyping were performed in a Midwestern American cohort of 105 HCV infected subjects among which 49 cleared HCV infection and 56 had persistent viral infection. A new protective association of HLA-Cw*05 to HCV infection of all ethnic populations was identified (OR = 0.12, 95% CI = 0.01-0.97, P = 0.03). It was surprising that HLA-A*02 (P for interaction = 0.02) and HLA-DRB1*12 (P for interaction = 0.05) showed statistical interaction with race indicating opposite associations in Caucasians (OR = 2.74 for A*02 and 2.15 for DRB1*12) and non-Caucasians (OR = 0.41 for A*02 and 0.15 for DRB1*12). In addition, HLA-DRB1*01 (OR = 0.26), DQB1*05 (OR = 0.23) and the haplotype DRB1*01-DQB1*05 (OR = 0.19) showed strong associations with viral clearance in Caucasians. The protective associations of A*03 (OR = 0.20) and DQB1*03 (OR = 0.20) were exclusive to non-Caucasians. In contrast, DQB1*02 (OR = 2.56, 95% CI = 1.15-7.71, P = 0.02) and the haplotype DRB1*07-DQB1*02 (OR = 5.25, 95% CI = 1.04-26.6, P = 0.03) were risk markers in Caucasians.The associations of HLA-A*02 and HLA-DRB1*12 with HCV infection are opposite with different races. HLA-A*03, Cw*05, DRB1*01, DQB1*03 and DQB1*05 are associated with viral clearance while HLA-DRB1*07 and DQB1*02 are risk markers for viral persistence of HCV infection in Midwestern Americans. These results reveal ethnically and geographically different distribution of HLA-genes which are associated with the outcome of HCV infection.