Background: Tumour necrosis factor-alpha (TNF-a) is an important proinflammatory cytokine driving axonal degeneration and retinal ganglion cell apoptosis in glaucoma. The aim of the study was to evaluate the association of TNF-a -308 G/A and -238 G/A polymorphisms with primary open-angle glaucoma (POAG). Design: A prospective, casecontrol study, university hospital setting. Participants: Eighty-six POAG patients and 193 healthy unrelated controls. Methods: TNF-a polymorphisms were screened by using direct gene sequencing. Main Outcome Measures: Frequency of TNF-a -308 G/A and TNF-a -238 G/A promoter polymorphisms in glaucoma and healthy subjects. Results: The frequencies of TNF-a -308 GA genotype and A allele were higher in patients with POAG (22.1% and 12.2%, respectively) in comparison with the control group (10.9% and 6%, respectively) (P = 0.046 and 0.02, respectively), with odds ratios of 2.45 (P = 0.01, 95% CI = 1.234.87) and 2.19 (P = 0.013, 95% CI = 1.184.08), respectively. Genotype distribution of the TNF-a -238 variants did not yield a statistically significant difference between the two groups (P = 0.87). Conclusion: TNF-a -308 G/A polymorphism seems to be associated with POAG in Turkish population. However, population-based studies with large number of subjects and long-term follow-up are needed to verify the association of TNF-a -308 G/A polymorphism with glaucoma susceptibility.