Progressive multifocal leukoencephalopathy (PML) is the most common clinical presentation of JC virus-associated CNS disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under treatment with natalizumab, especially in cases where cerebellar atrophy can be visualized by MRI. ANN NEUROL 2013. © 2013 American Neurological Association.