Introduction: Prevision of conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) is required to avoid unnecessary use of immunomodulating agents and to recognize patients with high disease activity. Our aim was to evaluate the value of phosphorylated neurofilament heavy chain (pNFH, a marker for neuroaxonal degeneration) and  Cyclic adenosine monophosphate response element‑binding protein (cAMP response element‑binding protein [CREB], a marker for neuroregeneration) levels in the prediction of conversion from CIS to MS. Methods: Twenty‑three consecutively recruited treatment‑naïve CIS patients were followed for 36 months. pNFH and CREB levels were measured in the first episode cerebrospinal fluid (CSF) and the serum of 12 converting (CIS‑MS) and 11 nonconverting CIS patients (CIS‑CIS) by enzyme‑linked immunosorbent assay. Results: Baseline CSF but not serum samples of CIS‑CIS patients displayed significantly lower pNFH levels compared to patients with CIS‑MS. The analysis of receiver operating characteristic curve presented a high specificity for the prediction of MS conversion for the CSF pNFH cut‑off level of 730.9 pg/ml. CSF pNFH levels significantly correlated with serum and CSF CREB levels. Higher baseline CSF pNFH and CREB levels were associated with more rapid progression to MS or increased disability scores. Conclusion: CSF pNFH measurement may potentially determine MS patients with unfavorable clinical progression after the first attack. pNFH and CREB appear to be increased in parallel in CSF of CIS patients with higher disease activity. These results suggest that neurofilaments are not only indicators of axonal degeneration but also partly a marker of neuronal differentiation and new axon regeneration mediated by CREB signaling pathway.