A Lewis(y) (Le(y)) tetrasaccharide modified by an artificial aminopropyl spacer was synthesized by a highly convergent approach that employed a levulinoyl ester and a 9-fluorenylmethoxycarbonate for temporary protection of the hydroxy groups and a trichloroethyloxycarbonyl as an amino protecting group. The artificial aminopropyl moiety was modified by a thioacetyl group, which allowed efficient conjugation to keyhole limpet hemocyanin (KLH) modified by electrophilic 4-(maleimidomethyl)cyclohexane-1-carboxylate (MI). Mice were immunized with the KLH-MI-Le(y) antigen. A detailed analysis of sera by ELISA established that a strong immunoglobulin G (IgG) antibody response was elicited against the linker region. The use of a smaller and more flexible 3-(bromoacetamido)propionate for the attachment of Le(y) to KLH not only reduced the IgG antibody response against the linker but also led to a significantly improved immune response against the Le(y) antigen. This study shows that highly antigenic linkers suppress antibody responses to weak antigens such as self-antigens.