To compare plasma homocysteine concentrations among patients with exfoliation syndrome, exfoliative glaucoma, normal-tension glaucoma, and normal control subjects without vascular or inflammatory ocular disease or glaucoma. Cross-sectional study. We tested 25 patients with exfoliation syndrome, 50 with exfoliative glaucoma, 25 with normal-tension glaucoma, and 24 control subjects. Fasting plasma homocysteine concentrations were measured by fluorescence polarization immunoassay. Patients using vitamin supplements or medications known to alter serum homocysteine were excluded. Homocysteine levels were higher in both exfoliatin groups compared with controls (exfoliation syndrome: P =.003; exfoliative glaucoma: P =.009); levels in normal-tension glaucoma were higher than but not significantly different from those in controls (P =.2). Hyperhomocysteinemia was present in 16 of 25 (64%) exfoliation syndrome patients, 28 of 50 (56%) exfoliative glaucoma patients, 13 of 25 (52%) normal-tension glaucoma patients, and 7 of 24 (29.2%) controls (P =.005). Multiple logistic regression analyses comparing exfoliation syndrome and exfoliative glaucoma patients with controls indicated that elevated plasma homocysteine concentration was a significant risk factor for exfoliation syndrome, in both those patients (odds ratios per 1.0 micromol/l increase in plasma homocysteine concentrations = 1.47; 95% confidence interval [CI] = 1.08-2.0) and in exfoliative glaucoma patients (odds ratio = 1.3; 95% CI = 1.07-1.6). Although exfoliative glaucoma and normal-tension glaucoma patients were not significantly different with respect to hyperhomocysteinemia, logistic regression modeling of exfoliative glaucoma vs normal-tension glaucoma patients showed that an increased homocysteine concentration was a significant risk factor for exfoliation syndrome in the presence of glaucoma (odds ratio per 1.0 micromol/l increase in homocysteine = 1.2, 95% CI = 1.0-1.4). These relationships were not affected by adjustment for potential confounding due to sex, history of hypertension, or other factors. Elevated plasma homocysteine, a risk factor for cardiovascular disease, is more common in exfoliation syndrome and exfoliative glaucoma patients than healthy controls. Patients with exfoliation syndrome may benefit from measurement of homocysteine levels.