Clinically isolated syndrome (CIS) represents the earliest phase of multiple sclerosis (MS). This study tested whether biomarkers for axonal degeneration can improve upon sensitivity and specificity of magnetic resonance imaging (MRI) parameters in predicting conversion from CIS to MS. Patients with CIS ( n=52), relapsing-remitting MS (RRMS, n=38) and age-matched controls ( n=25) were included. Cerebrospinal fluid (CSF) levels of tau and neurofilaments (NfH^SMI35) were measured using ELISA. The MRI T2-lesion load and the Expanded Disability Status Scale (EDSS) were recorded. CSF tau and NfH^SMI35 were elevated in CIS compared to controls (p<0.05). RRMS patients with acute relapse had higher NfH^SMI35 levels than stable patients. Tau and NfH^SMI35 levels correlated with EDSS in CIS and RRMS. In RRMS, the number of T2-lesions correlated with tau levels ( R=0.53, P=0.01). The sensitivity predicting the conversion from CIS to MS was higher for the combination of CSF markers (either tau or NfH^SMI35 elevated) than for MRI (40 versus 34%), but could be further increased to 60% if CSF and MRI criteria were combined. Similarly, the combination of tau and NfH^SMI35 showed higher specificity (94%) than MRI (82%). Tau and NfHSMI35 are valuable biomarkers for axonal damage in the CIS patients. Predicting conversion from CIS to MS can be improved if CSF markers are combined with MRI.