Primary open-angle glaucoma (POAG) is an optic neuropathy that has a high worldwide prevalence and that shows strong evidence of complex inheritance. The myocilin (MYOC) gene is the only one that has thus far been shown to have mutations in patients with POAG. Apolipoprotein E (APOE) plays an essential role in lipid metabolism, and the APOE gene has been involved in neuronal degeneration that occurs in Alzheimer disease (AD). Here, we report that two APOE-promoter single-nucleotide polymorphisms (SNPs) previously associated with AD also modify the POAG phenotype. APOE(−219G) is associated with increased optic nerve damage, as reflected by increased cup:disk ratio and visual field alteration. In addition, APOE(−491T), interacting at a highly significant level with an SNP in the MYOC promoter, MYOC(−1000G), is associated with increased intraocular pressure (IOP) and with limited effectiveness of IOP-lowering treatments in patients with POAG. Together, these findings establish APOE as a potent modifier for POAG, which could explain the linkage to chromosome 19q previously observed by use of a genome scan for this condition and an increased frequency of glaucoma in patients with AD. The findings also shed new light on potential mechanisms of optic nerve damage and of IOP regulation in POAG.