Progressive multifocal leukoencephalopathy (PML) generally occurs in patients with impaired cellular immunity. Monoclonal antibodies also predispose the patient to PML as they depress the immune system. PML was classically characterized by a lack of inflammation and absence of gadolinium enhancement. However, gadolinium enhancement of PML lesions was first described in HIV-positive patients under therapy. We present a case of gadolinium enhanced PML lesions occuring after natalizumab monotherapy of a relapsing multiple sclerosis. Radiologists must be aware of this particular feature, as confirmation of the diagnostic of PML becomes more challenging. Namely, distinction between starting PML and multiple sclerosis enhanced additional active lesion is difficult and diagnosis must be established by combined analysis of full clinical evolution, brain MRI scans, and polymerase chain reaction of cerebrospinal fluid.