Purpose: To evaluate the individual and interactive effects of polymorphisms in the myocilin (MYOC), optineurin (OPTN), WD repeat domain 36 (WDR36), and apolipoprotein E (APOE) genes on primary open-angle glaucoma (POAG) in northern Chinese. Methods: Northern Chinese study subjects, 176 POAG patients and 200 controls, were recruited for screening of the coding exons and splicing regions of MYOC. Five single nucleotide polymorphisms (SNPs) in OPTN (M98K, R545Q, IVS5+38T>G, IVS8-53T>C, and IVS15+10G>A), one SNP in WDR36 (IVS5+30C>T) as well as the APOE promoter and epsilon 2/epsilon 3/epsilon 4 polymorphisms were also examined. Association analysis was performed by using chi(2) analysis. High-order gene-gene interaction was also analyzed using the multifactor dimensionality reduction (MDR) method. Results: In MYOC, 22 variants were identified. Four of them were novel but found in controls only. The missense mutation, Val53Ala, is likely a glaucoma causing mutation, accounting for 0.6% of cases. No individual polymorphism in OPTN, WDR36, or APOE was associated with POAG. MDR analysis identified a best 6-factor model for POAG: MYOC IVS2+35A>G, OPTN Met98Lys, OPTN IVS5+38T>G, OPTN IVS8-53T>C, WDR36 IVS5+30C>T, and APOE -491A>T. Conclusions: The association pattern between the genes, MYOC, OPTN, WDR36, and APOE, and POAG in northern Chinese is different from that of southern Chinese. Disease-causing mutations in MYOC accounted for a small proportion of northern Chinese POAG patients. Common polymorphisms in these genes were not associated with POAG individually but might interactively contribute to the disorder, supporting a polygenic etiology.