Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system. It is caused by the JC virus (JCV), a human polyomavirus replicating in human glial cells. PML is the result of the reactivation of latent JCV infection that usually occurs in the setting of cellular immunodeficiencies such as HIV-1 infection. Epidemiologic data suggest that the impact of highly active antiretroviral therapy (HAART) on the incidence of PML is less profound than seen with other opportunistic infections. Given the lack of an effective and specific therapy for PML, HAART remains the only therapeutic option in patients with PML. However, a significant number of cases appear unresponsive to antiretroviral therapy. Moreover, there is growing data on unexpected inflammatory cases of PML after initiation of HAART. Thus, PML will remain a relevant cause of morbidity and mortality in HIV- 1-infected patients. Here we report two cases of PML, along with a concise review of the literature on this important disease.