Nonarteritic anterior ischemic optic neuropathy (AION) is a well-described entity that is believed to be caused by abnormal anatomy of the optic disc and to be precipitated by several stressors or disease states. Activated protein C resistance (APCR) is a recently described mutation of factor V (FV) gene that renders FV resistant to cleavage by activated protein C. APCR predisposes to thrombotic events. The case of a 61-year-old woman with AION and activated protein C resistance is presented, and the management is discussed. We thoroughly review the literature on these two conditions. We propose that a prospective analysis of the potential role of APCR in some cases of AION is needed and suggest that physicians consider this and other prothrombotic states when evaluating patients with AION.