Our study demonstrates that apoptosis occurs in oligodendrocytes associated with demyelinated lesions of patients with both HIV-associated and non-HIV-associated PML. There were no differences in degree, location, or type of infected or apoptotic cells between patients with HIV-associated and non-HIV-associated PML. The extent of apoptosis did not correlate with the presence or intensity of host inflammatory response. Accumulation of viral particles in nuclei of infected cells made it difficult to identify morphologic changes in the nucleus typically associated with apoptosis.