PURPOSE. Recently, several studies have investigated genetic associations between Cytochrome P450 (CYP1B1), Endothelial nitric oxide synthase (eNOS), and Neurotrophin-4 (NTF4) with primary angle-closure glaucoma (PACG) in various ethnic groups. We investigated the association of these candidate genes with PACG in samples from Australia and Nepal. METHODS. A total of 235 patients with PACG (106 Nepalese and 129 Australian) and 492 controls (204 Nepalese and 288 Australian) was included. Tag single nucleotide polymorphisms (SNPs) were selected to cover the majority of common variation within the candidate genes and genotyped in DNA extracted from peripheral whole blood. Allele and haplotype analyses were conducted in PLINK. Bonferroni correction was applied for the total number of SNPs in this study (P=0.05/15 = 0.003). RESULTS. In the Australian cohort, one eNOS SNP rs3793342 showed significance association with PACG after Bonferroni correction (P value of 0.003, odds ratio [OR] 0.5, 95% confidence interval [CI] 0.3-0.8). After adjusting the results for sex and age, SNPs rs3793342 and rs7830 showed significance after Bonferroni correction (P value of 0.001 and 0.003, respectively). The eNOS haplotype of all 7 typed SNPs showed significant association with a global P value of 0.019, with the CGCAATC haplotype giving a specific P value of 0.008 and OR of 1.5 (95% CI 0.9-2.4). In the Nepalese cohort, SNPs in CYP1B1 and NTF4 genes showed borderline association with PACG, but did not survive Bonferroni correction. CONCLUSIONS. Our data support the involvement of common variations in eNOS with PACG pathogenesis. Differences were observed in the two populations studied, and additional replication studies in other populations are necessary to confirm these associations.