Purpose. A Tyr-to-His (Y402H) sequence variant in the factor H (FH) and factor H-like protein (FHL-1) gene is strongly associated with an increased susceptibility for age-related macular degeneration (AMD). The purpose of this study was to understand how the Y402H variant in FH/FHL-1 contributes to the pathogenesis of AMD and' in particular' whether interactions mediated by FH/FHL-1' including binding to C-reactive protein (CRP), group A streptococcal M protein (GAS M6), heparin, and retinal pigment epithelial cells (RPE)' are affected. Methods. FH was purified from sera of patients homozygous for FH(Y402) or (H402)' and recombinant FH fragments representing FHL-1 were generated. Proteins were analyzed for binding to CRP' GAS M6' heparin' and RPE cells. Results. Binding of the FH and FH1 to seven polymorphic variants to CRP and M protein was reduced. The variant did not influence the interaction of FH with heparin but did reduce binding of FHL-1. Binding of the FH and FHL-1 polymorphic variant to RPE cells was not affected. Conclusions. The FH Y402H polymorphism associated with AMD causes a reduction in binding of FH and FHL-1 to CRP and M protein. Both variants show comparable binding to RPE cells' indicating that AMD is unlikely to manifest as a result of impaired host cell-surface recognition. The decreased interaction between FH and CRP' which is essential for the anti- inflammatory function of CRP, provides a possible pathophys- iological explanation for the association of the Y402H variant with AMD.