Progressive multifocal leukoencephalopathy (PML) is a viral demyelinating disease due to the reactivation of the JC virus (JCV), which usually occurs in the context of immunosuppression in HIV infection, malignancy, or in patients on disease modifying therapy for autoimmune diseases, such as multiple sclerosis (MS) and Crohn's disease. Notably, there is growing recognition that PML can occur in patients with transient immune dysfunction. Here, we present a case of a 55-year-old man without history of immunosuppression or evidence of ICL who was diagnosed with PML on brain biopsy. We will discuss the potential etiologies of mild and transient immunosuppression that can lead to PML with non-apparent immunosuppression.