<h3>Objective:</h3> Describe a case of a woman with mixed cryoglobulinemia who presented with progressive weakness and biopsy proven systemic vasculitis in the setting of Hepatitis C virus (HCV) negative serology. <h3>Background:</h3> The disease expression of mixed cryoglobulinemia vasculitis caused by HCV infection triggers the downstream B-cell arm of autoimmunity. <h3>Design/Methods:</h3> A 61 year old woman with a history of HCV infection, mixed cryoglobulinemia, mononeuritis multiplex secondary to nervous system vasculitis affecting peripheral nerves and hypertension presented with weakness that progressed to quadriparesis and neurocognitive decline over a period of eight months. <h3>Results:</h3> MRI examination of the brain showed bilateral ventral pontine lesions extending into the middle cerebellar peduncles, ventrolateral midbrain and cerebral peduncles as well as bilateral cortical frontal lobe lesions. Also present were intrinsic mixed intensity DWI/ADC lesions of undetermined etiology and extensive subcortical and periventricular white matter hyperintensities. CT angiography of her head and neck showed large vessel intracranial vasculopathy involving the bilateral MCA branches. Conventional angiogram, however, did not show any evidence of angiographic vasculitis. MRI spectroscopy was non-diagnostic. MRI of the neuroaxis showed a small focus of linear non-enhancing hyperintense lesion at the level of C3. EMG demonstrated severe generalized sensory-motor polyneuropathy with severe axonal loss. EEG showed mild to moderate diffuse slowing. CSF evaluation was negative, HCV viral load was undetectable, connective tissue markers (Anti-dsDNA, Anti-SCL70, Anti-CENTR, Anti-RNP, Anti-Smith, Anti-SSA/SSB, ANCA) were negative and the remaining serology was significant for elevated ESR, CRP, low C4 complements, positive anti-AQP4 antibodies titers (1:2560) and positive myelin basic protein. Brain biopsy showed perivascular lymphocytic inflammation, confirming vasculitis. Our patient completed courses of high dose steroids, IVIG and Rituximab with mild improvement in motor strength. <h3>Conclusions:</h3> Although an atypical feature of NMO, cryoglobulinemia with production of anti-AQP4 antibodies may, in part, contribute to development of a demyelinating process. <b>Disclosure:</b> Dr. Esechie has nothing to disclose. Dr. Harazeen has nothing to disclose. Dr. Rivera Vega has nothing to disclose. Dr. Thottempudi has nothing to disclose. Dr. Chhabra has stock in Pfizer. Dr. Chhabra has stock in Biogen. Dr. Chhabra has stock in Johnson and Johnson. Dr. Chhabra has stock in Medtronic. Dr. Shaltoni has nothing to disclose. Muhammad Zeeshan Memon, MD has nothing to disclose. Dr. Patel has nothing to disclose. Dr. Wu has nothing to disclose.