Background: Previous magnetic resonance imaging (MRI) studies have demonstrated increased iron deposition in the basal ganglia of multiple sclerosis (MS) patients. However, it is not clear whether these alterations are associated with changes of iron metabolism in body fluids. Objectives: The purpose of this study was to investigate if iron metabolism markers in cerebrospinal fluid (CSF) and serum of clinically isolated syndrome (CIS) and MS patients differ from controls and how they relate to clinical and imaging parameters. Methods: We analysed serum ferritin, transferrin and soluble transferrin-receptor and CSF ferritin and transferrin by nephelometry in non-anaemic CIS ( n=60) or early MS ( n=14) patients and 68 controls. In CIS/MS we additionally assessed the T2 lesion load. Results: CSF transferrin was significantly decreased in CIS/MS compared to controls ( p<0.001), while no significant differences were seen in serum. Higher CSF transferrin levels correlated with lower physical disability scores ( r= −0.3, p<0.05). CSF transferrin levels did not correlate with other clinical data and the T2 lesion load. Conclusion: Our biochemical study provides evidence that altered iron homeostasis within the brain occurs in the very early phases of the disease, and suggests that the transporter protein transferrin may play a role in the increased iron deposition known to occur in the brain of MS patients.