Immunoglobulin GM allotypes are associated with the outcome of several infections, including hepatitis C virus (HCV) infection, but the underlying mechanisms are not known. HCV employs sophisticated strategies to evade host immunosurveillance. One such strategy might involve the scavenging of the Fc gamma domain of the anti-HCV IgG antibodies by its Fc gamma receptor-like site formed by HCV core protein, potentially interfering with the Fc gamma-mediated host defense mechanisms. We tested the hypothesis that GM allotypes modulate this viral strategy through differential binding to the core protein. Here we show that the absorbance values for binding to the HCV core protein were significantly higher for IgG1 with GM 3 allotype than that for the allelic GM 1,2,17 determinants (p=0.0003). These results provide a mechanistic explanation for the involvement of GM allotypes in the outcome of HCV infection. These findings also shed light on the possible evolutionary selective mechanism that maintains GM polymorphism.