Background: Nitric oxide (NO), hydroxyl radical (OH.), superoxide anion (02) and hydrogen peroxide (H2O2) are free-radicals released in oxidative stress. Superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase (CAT) are antioxidant enzymes, mediating defense against oxidative stress. Excess NO and/or defective antioxidants cause lipid peroxidation, cellular dysfunction and death. Age-related maculopathy (ARM) or degeneration (ARMD) is the leading cause of irreversible blindness in developed countries. The etiology is unclear and the molecular factors contributing this disease remain to be specified. Aims: This multicenter, double-blind, cross-sectional study aimed to investigate plasma NO and lipid peroxidation levels with relation to antioxidant enzyme activities in erythrocyte and plasma of patients with ARMD compared with healthy control subjects. Methods: NO, lipid peroxidation (measured as plasma malondialdehyde [MDA] levels) and the catalytic activity of SOD, GSHPx and CAT were measured in a group of 41 patients with maculopathy (19 men, 22 women; 67.12 +/- 3.70 years) and compared with 25 age- and sex-matched healthy control subjects without maculopathy (12 men, 13 women; 68.04 +/- 3.02 years). NO and MDA levels were measured in plasma, CAT in red blood cells (RBCs), and SOD and GSHPx in both plasma and RBCs. Color fundus photographs were used to assess the presence of maculopathy, and the patients were divided into two groups using clinical examination and grading of photographs; early-ARM (n = 22) and late-ARMD (n = 19). Results: All patients with maculopathy had significantly (p < 0.001) higher plasma NO levels over control subjects (mean &PLUSMN;SD, 48.58 &PLUSMN; 8.81 vs. 28.22 &PLUSMN; 3.39 μmol/l). Plasma MDA levels in patients and control subjects were 4.99 &PLUSMN; 1.00 and 2.16 &PLUSMN; 0.24 μmol/l, respectively, and the difference was significant (p < 0.001). On the other hand, SOD and GSHPx activities were significantly lower in both RBCs and plasma of patients with maculopathy than in control subjects (RBCs-SOD, 3509.30 +/- 478.22 vs. 5033.30 +/- 363.98 U/g Hb. p < 0.001; plasma-SOD, 560.95 &PLUSMN; 52.52 vs. 704.76 &PLUSMN; 24.59 U/g protein, p < 0.001; RBCs-GSHPx, 663.43 +/- 41.74 vs. 748.80 +/- 25.50 U/g Hb, p < 0.001; plasma-GSHPx, 98.26 &PLUSMN; 15.67 vs. 131.80 &PLUSMN; 8.73 U/g protein, p < 0.001). RBCs-CAT levels were not different between groups (131.68 +/- 12.89 vs. 133.00 +/- 13.29 k/g Hb, p = 0.811). Late-ARMD patients had significantly lower antioxidant enzyme levels and higher MDA levels when compared with early-ARM patients (for each, p < 0.001). In addition, plasma NO and MDA levels were negatively correlated with SOD and GSHPx activities. Conclusions: This study demonstrated for the first time that NO, the most abundant free-radical in the body, might be implicated in the pathophysiology of ARMD in association with decreased antioxidant enzymes and increased lipid peroxidation status.