Cerebral vasculopathy due to varicella-zoster virus (VZV) infection is well-documented. We report a fatal case of VZV multifocal vasculopathy in a patient with systemic lupus erythematosus (SLE) who presented with subacute changes in mental status and had multiple areas of hemorrhagic infarcts on brain imaging. However, the correct diagnosis was delayed by several confounding factors including the absence of zoster rash, normal cerebral angiography, persistently low cerebrospinal fluid (CSF) glucose and negative initial polymerase chain reaction (PCR) for VZV DNA in the CSF. Our case and literature review suggests that the sensitivity of PCR for VZV DNA in the CSF is low in VZV vasculopathy and clinical suspicion of this disease in the setting of characteristic imaging findings could be crucial to timely diagnosis.