Fifteen variants in 10q26 are in strong linkage disequilibrium and are associated with an increased risk for age-related macular degeneration (AMD), a frequent cause of blindness in developed countries. These variants tag a single-risk haplotype encompassing the genes ARMS2 (age-related maculopathy susceptibility 2) and part of HTRA1 (HtrA serine peptidase 1). To define the true AMD susceptibility gene in 10q26, several studies have focused on the influence of risk alleles on the expression of ARMS2 and/or HTRA1, but the results have been inconsistent. By heterologous expression of genomic ARMS2 variants, we now show that ARMS2 mRNA levels transcribed from the risk haplotype are significantly reduced compared with non-risk mRNA isoforms. Analyzing variant ARMS2 constructs, this effect could specifically be assigned to the known insertion/deletion polymorphism (c.(*)372_815del443ins54) in the 3'-untranslated region of ARMS2. Reporter gene assays with HTRA1 promoter sequences demonstrated the presence of a Müller glia-specific cis-regulatory region further upstream of the transcription start site. However, AMD risk alleles had little or no effect on HTRA1 promoter activity in the retina. Analysis of a large series of human post-mortem retina/retinal pigment epithelial samples heterozygous for the risk haplotype confirmed the in vitro/ex vivo results and demonstrated that the risk haplotype affects ARMS2 but not HTRA1 mRNA expression. Furthermore, we provide in vivo evidence that a common non-risk-associated non-synonymous variant (rs2736911) also leads to decreased ARMS2 transcript levels. Consequently, our data suggest that pathogenic effects due to ARMS2 protein deficiency are unlikely to account for AMD pathology.