Background: Tumour necrosis factor-alpha (TNF-α) 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-α -308 G/A and -238 G/A polymorphisms with primary open-angle glaucoma (POAG). Design: A prospective, case-control study, university hospital setting. Participants: Eighty-six POAG patients and 193 healthy unrelated controls. Methods: TNF-α polymorphisms were screened by using direct gene sequencing. Main Outcome Measures: Frequency of TNF-α -308 G/A and TNF-α -238 G/A promoter polymorphisms in glaucoma and healthy subjects. Results: The frequencies of TNF-α -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=1.23-4.87) and 2.19 (P=0.013, 95% CI=1.18-4.08), respectively. Genotype distribution of the TNF-α -238 variants did not yield a statistically significant difference between the two groups (P=0.87). Conclusion: TNF-α -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-α -308 G/A polymorphism with glaucoma susceptibility. © 2011 The Authors. Clinical and Experimental Ophthalmology © 2011 Royal Australian and New Zealand College of Ophthalmologists.