Hippocampal ischemia is a rare complication of cocaine abuse that has been thought to arise from vasospasm, anoxic injury, and/or catecholaminergic excitotoxicity. We present two cases of patients abusing cocaine, who presented with an acute onset anterograde amnesia due to bilateral hippocampal ischemia, and had different outcomes. Case 1 is a 49-year-old male with a history of IV heroin abuse who presented after being found down for an unknown period of time. He awoke with no memory of events leading up to hospitalization and was unable to retain new information. Urine toxicology was positive for cocaine and opiates. Traditional vascular risk factors included obesity, hypertension, and hyperlipidemia. His recovery was complicated by continued drug use and one episode of cardiac arrest. Despite cognitive rehabilitation, only minimal improvements in his anterograde memory were observed during his annual follow-up. Case 2 is a 23-year-old male with a history of attention deficit disorder treated with dexmethylphenidate and a history of consistent marijuana and cocaine abuse, who presented with nausea, vomiting, chest pain, shortness of breath, and acute-onset short-term memory loss. Urine toxicology was negative for cocaine and opiates and positive for marijuana. He had no known vascular risk factors. With cognitive rehabilitation and discontinuation of illicit drug use, he demonstrated a significant improvement in his memory function over the course of six months. Brain MRI in both patients showed symmetric bilateral hippocampal diffusion restriction without post-contrast enhancement with corresponding hyperintensities on fluid-attenuated inversion recovery sequences. In both patients, cerebrospinal fluid (CSF) studies were unremarkable for inflammation or infection, and electroencephalograms were normal in awake and drowsy states. Bilateral hippocampal ischemia should be considered as a potential cause of acute onset anterograde amnesia in patients with a history of cocaine abuse. Other substances such as heroin and dexmethylphenidate may potentially increase susceptibility for hippocampal ischemia in patients using cocaine. Discontinuation of illicit drug abuse can influence the degree of recovery from acute bilateral hippocampal ischemia.