Progressive multifocal leukoencephalopathy (PML) has been traditionally associated to severe immunosuppression and described mainly in highly active antiretroviral therapy (HAART)-naïve patients with a low lymphocyte CD4+ count. In the last years, some cases of PML have been described in HIV patients with a higher CD4+ count shortly after initiation of HAART and in association with the immune reconstitution inflammatory syndrome (IRIS). We report on a rare case of PML, not IRIS associated, that occurred in a HIV-positive patient with a lymphocyte CD4+ count greater than 700/µl and with an undetectable HIV viral load resulting from a long-term HAART. We describe the pathological and the ultrastructural features of the brain lesion. This case confirms that a severe immunosuppression or an IRIS is not required for the development of PML in HIV positives. The diagnosis of PML should always be considered in patients with consistent neurological symptoms, even with a high lymphocyte CD4+ level and a full viral suppression resulting from a long-term HAART.