Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are leading causes of blindness in aging populations. This study was conducted to investigate the associations of chromosome 6p21.3 region, including CFB-SKIV2L-TNXB-FKBPL-NOTCH4 genes, with both neovascular AMD and PCV. Six single nucleotide polymorphisms (SNPs) in this region and two known AMD-associated SNPs in CFH (rs800292) and HTRA1 (rs11200638) were genotyped in a Han Chinese cohort composed of 490 neovascular AMD patients, 419 PCV patients and 1316 controls. Among the SNPs, TNXB rs12153855 and FKBPL rs9391734 conferred an increased susceptibility to neovascular AMD (P = 2.8 × 10(-4) and 0.001, OR = 1.80 and 1.76, respectively), while SKIV2L exerted a protective effect on neovascular AMD (P = 2.2 × 10(-4), OR = 0.49). Rs12153855C and rs9391734A alleles could further increase the susceptibility to AMD in subjects with rs800292, rs11200638 and rs429608 risk alleles. However, only the association of SKIV2L rs429608 remained significant after adjusting for rs800292, rs11200638 and the other 5 SNPs. The protective haplotype AATGAG exhibited significant association with neovascular AMD (permutation P = 0.015, OR = 0.34). None of the SNPs in this region was associated with PCV. Association profiles of 6p21.3 region showed discrepancy between neovascular AMD and PCV, indicating possible molecular and pathological differences between these two retinal disorders.