Purpose. To assess the effects of antioxidant oral supplementation based on docosahexaenoic acid (DHA) in pseudoexfoliative (PEX) glaucoma. Patients and Methods. A prospective 6-month open-label randomized controlled trial was conducted in patients with PEX glaucoma and adequate intraocular pressure (IOP) control. Patients in the DHA group received a high-rich DHA (1 g) nutraceutical formulation. Ophthalmological examination, DHA erythrocyte membrane content (% total fatty acids), plasma total antioxidant capacity (TAC), plasma malondialdehyde (MDA), and plasma IL-6 levels were assessed. Results. Forty-seven patients (DHA group 23, controls 24; mean age 70.3 years) were included. In the DHA group, the mean IOP in the right eye decreased from 14.7 3.3 mmHg at baseline to 12.1 1.5 mmHg at 6 months (P=0.01). In the left eye, IOP decreased from 15.1 3.3 mmHg at baseline to 12.2 2.4 mmHg at 6 months (P=0.007). DHA erythrocyte content increased in the DHA group, with significant differences versus controls at 3 months and 6 months (8.1% 0.9 vs. 4.4% 0.7; P<0.0001). At 6 months and in the DHA group only, TAC levels as compared with baseline increased significantly (919.7 117.9 vs. 856.9 180.3 µM copper-reducing equivalents; P=0.01), and both MDA (4.4 0.8 vs. 5.2 1.1 nmol/mL; P  =  0.02) and IL-6 (2.8 1.3 vs. 4.7 2.3 pg/mL; P=0.006) levels were lower than in controls. Conclusions. Targeting pathophysiology mechanisms of PEX glaucoma by reducing oxidative stress and inflammation with a high-rich DHA supplement might be an attractive therapeutic approach. Despite the short duration of treatment, decrease in IOP supports the clinical significance of DHA supplementation.