Common genetic variation in the complement component 1 inhibitor gene (SERPING1) was recently reported to increase the risk of developing age-related macular degeneration (AMD). This study was performed to replicate the association between SERPING1 and AMD.Seven single nucleotide polymorphisms (SNPs) tagging common haplotypes across SERPING1 were genotyped on 786 (The Mayo Clinic) subjects and the association with AMD studied using single SNP and haplotype association analyses. The SNP in intron 6 (rs2511989) previously reported to increase the risk of AMD was studied in an additional 1,541 subjects from the Age-Related Eye Disease Study (AREDS). Association with specific subtypes of AMD and interaction with four other loci: complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2/LOC387715), High Temperature Requirement Factor A1 (HTRA1), complement factor B/complement component 2 (CFB/C2), and complement component 3 (C3) involved in AMD was explored.The seven tag-SNPs were not associated with AMD in the Mayo subjects (p=0.13-0.70) and rs2511989 was also not associated with AMD in the Mayo or AREDS subjects (p=0.44-0.45). Evaluation of haplotypes across SERPING1 did not reveal association with AMD (p=0.14-0.97). SNPs were not associated with AMD subtypes (early, geographic atrophy, or exudation). No interaction with other AMD risk variants was observed.We were unable to replicate the reported association between SERPING1 and AMD in two independent groups of subjects.