Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing the CFH and CFHR genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of Factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (P-value=1.84x10-6), FHR-2 (P-value=1.47x10-4), FHR-3 (P-value=1.05x10-5) and FHR-4A (P-value=1.22x10-2) in AMD, whereas FH levels remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein levels (e.g. FH p.Tyr402His and FHR-2 levels, P-value=3.68x10-17), while the association with FH levels was limited. Furthermore, in a cohort of 17,596 controls and 15,894 individuals with AMD of the International AMD Genomics Consortium, we found that low-frequency and rare protein-altering variants in CFHR2 and CFHR5 associated with AMD independently of all previously reported GWAS signals (P-value=5.03x10-3 and P-value=2.81x10-6, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 protein levels (e.g. p.Cys72Tyr in CFHR2 and FHR-2, P-value=2.46x10-16). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins may be effective to treat or prevent progression of AMD. Such therapies could target specific individuals with AMD based on their genotypes at the CFH locus.