Background: Neurosurgeons are frequently among the first physicians asked to evaluate patients with papilledema, and the patient is often referred with the implication that they may require shunting. After an initial evaluation to exclude potential neurosurgical emergencies, the physician should carefully consider various etiologies of papilledema to prevent unnecessary neurosurgical operations. Case Description: The authors report two illustrative cases of unusual causes of papilledema: Anemia and leukemic infiltration of the central nervous system. In each case, a complete blood count provided clues for the diagnosis. A review of the literature is also included. Conclusions: Both patients responded to medical management/treatment of the underlying disease and did not require neurosurgical operative intervention. Papilledema may be caused by other etiologies besides increased intracranial pressure. The authors present two unusual cases leading to papilledema and provide an outline for the workup of these conditions.