Little is known about the role of genetic variants in the early stages of age-related macular degeneration (AMD). We aimed to investigate how genetic variations within five well-defined genes relate to AMD severity.We analysed SNPs in the genes for complement factor H (CFH), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HtrA1), complement factor B (CFB), and complement component 2 (C2)in 183 controls and 730 patients with increasing severity of AMD from the Muenster aging and retina study (MARS). Severity scoring was based on the Rotterdam classification of fundus photographs.Compared with controls, patients with very early AMD showed a significantly increased minor allele frequency (MAF) only for CFH-rs1061170. With increasing severity of AMD, SNPs in CFH-rs1061170,as well as ARMS2-rs10490924, became consistently more common (P<0.001). Likewise, HtrA1-rs11200638 was less clearly associated with AMD severity, whereas C2-rs9332739 and CFB-rs641153 showed no relation. Multifactorial models confirmed CFH and ARMS2 as major determinants of AMD severity, whereas addition of HtrA1, C2 and CFB did not improve model prediction. In the models, age did not contribute to very early but to all more severe AMD stages, whereas smoking history had a significant impact only for late AMD.Our findings indicate that the CFH gene is involved in the onset of AMD, whereas both, the CFH and ARMS2 genes, and more weakly, the HtrA1 gene, appear to account for the advancement of AMD. The results for SNPs in the C2 and CFB genes were inconclusive. Genetic factors dominated in their impact over age and smoking history.