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The mechanisms for neurological complications of COVID-19, the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are not yet well understood. We present a critically ill man with a COVID-19-associated hemorrhagic encephalopathy. SARS-CoV-2 RNA was not detected in cerebrospinal fluid (CSF) or blood. CSF analyses suggested dysregulation of pro-inflammatory cytokine pathways, particularly tumor necrosis factor-α and interleukin-6, consistent with a cytokine release syndrome. The patient gradually recovered with supportive care and neurological rehabilitation. Awareness of this clinical entity may facilitate the identification of patients with a potentially remediable cause of encephalopathy in COVID-19., Graphical abstract Unlabelled Image, Highlights • COVID-19 is a rapidly evolving and deadly global pandemic. • Cytokine storm syndromes have been proposed as a cause for severe disease. • Neurological manifestations of COVID-19 are an area of active research. • Pro-inflammatory CSF cytokine dysregulation may mediate hemorrhagic encephalopathy. • Vigilance for this clinical condition is required as COVID-19 continues to spread.