An involvement of the peripheral nervous system is frequent in patients with HCV-related mixed cryoglobulinemia (HCV-MC), whereas central nervous system (CNS) impairment has been rarely reported. To investigate the possible CNS involvement in MC, we evaluated 18 patients by neurophysiological, neuroradiological and neuropsychological methods. Three patients (16.7%) had clinically evident neurological central signs, ten (55.5%) complained of mild symptoms, possibly indicative of CNS impairment, and five (27.8%) did not have any CNS symptom. Evoked potentials (EPs) were abnormal in 83% of the cases (SSEPs in 72%, VEPs in 44%, MEPs in 39% and BAERs in 22%). Brain magnetic resonance imaging (MRI) showed abnormal findings in 83% (small T2-weighted hyperintense lesions in 72%, focal or diffuse atrophy in 50%). Cognitive impairment was detected in 22% of the patients. A mild or subclinical CNS involvement is frequent in MC patients. Neuropsychological, neurophysiological and neuroradiological examination are useful to detect CNS involvement also in asymptomatic subjects.