To investigate whether recently described polymorphisms in the optic atrophy 1 gene (OPA1) are associated with primary open-angle glaucoma (POAG) with elevated intraocular pressure in the Caucasian, African-American, and Ghanaian (West African) populations.POAG was defined as the presence of glaucomatous optic nerve damage, associated visual field loss, and elevated intraocular pressure (>21 mm of mercury in both eyes). We used TaqMan allelic discrimination assays to genotype two single nucleotide polymorphisms (SNPs, rs10451941 and rs166850) in OPA1 in the Caucasian (279 cases, 227 controls), African American (193 cases, 97 controls), and Ghanaian (170 cases, 138 controls) populations. Allele, genotype, and haplotype frequencies were compared between the cases and controls from each population.There was no significant difference in OPA1 allele or genotype frequencies between POAG patients and controls at the rs10451941 and rs166850 SNPs in any population (p>0.05). Haplotype analysis also failed to demonstrate a significant association with POAG. The age-of-onset distribution in the Caucasian POAG patients was independent from genotypes at rs10451941.There was no association between two previously implicated OPA1 polymorphisms and a POAG phenotype that includes elevated intraocular pressure. This represents the first association analysis of OPA1 in high tension glaucoma in the African American and Ghanaian populations and is the largest study to date on the investigation of the potential association between OPA1 and POAG with elevated intraocular pressure. OPA1 association with POAG may be limited to patients with normal tension glaucoma in these populations.