In the context of 2 patients with hematological malignancy who developed progressive multifocal leukoencephalopathy (PML), we review the current therapeutic options for this serious complication. Both patients had lymphoma and had been pretreated with the antibody rituximab. Diagnosis of PML was obtained upon the detection of the JC virus. The outcome was fatal in both cases. So far, no standard therapeutic approach for JC virus infection has been established in HIV-negative patients with hematological malignancies and the outcome is usually fatal. Serotonin receptor antagonists might have a beneficial effect by blocking the virus from entering the cells. Although hopes for the efficacy of mefloquine were disappointed by the results of 1 study, several case reports describe improvements in neurological impairment when this drug is administered. Taking the desperate situation of this patient group into consideration, the combination of mirtazapine and mefloquine might be worthy of an attempt.