Objective: To determine whether genetic or acquired thrombophilias and other risk factors are associated with nonarteritic anterior ischemic optic neuropathy (NAION). Design: Retrospective case-control study. Participants: Sixty-one patients with NAION diagnosed between 1984 and 1997. Ninety consecutive patients who visited the Eye Institute made up the control group. Intervention: Protein C, protein S, antithrombin III, lupus anticoagulant, and three recently described prothrombotic polymorphisms (i.e., factor V G1691A, factor II G20210A, and methylenetetrahydrofolate reductase [MTHFR] C677T) were analyzed. In addition, risk factors for arteriosclerotic vascular disease were assessed. Main Outcome Measures: Parameters of thrombophilia. Results: None of the thrombophilic markers (genetic and acquired) constituted a significant risk factor for NAION. Ischemic heart disease, hypercholesterolemia, and diabetes mellitus were discerned as risk factors for NAION with odds ratios of 2.9 (95% confidence interval [CI], 1.3-6.4), 2.6 (95% CI, 1.2-5.5), and 2.3 (95% CI, 1.1-4.8), respectively. Multiple logistic regression analysis indicated that ischemic heart disease and hypercholesterolemia exerted an additive risk for NAION with a combined odds ratio of 4.5 (95% CI, 1.4-14.5). However, none of these risk factors statistically predicted second eye involvement. Conclusion: NAION was not found to be associated with thrombophilic risk factors, yet it was related to ischemic heart disease, hypercholesterolemia, and diabetes mellitus.