The objectives of this study were (1) to determine how cerebrospinal fluid (CSF) neurofilament heavy chain (NfH^SMI34 and NfH^SMI35) levels relate to clinical outcome in optic neuritis (ON) and multiple sclerosis (MS) relapse patients treated with high dose oral methylprednisolone; and (2) to correlate neurofilament and myelin basic protein (MBP) concentrations, particularly as the latter was previously associated with clinical disability. Fifty subjects participated in two double-blind, randomized, placebo-controlled clinical trials. Eight/18 patients in the ON trial and 15/32 subjects in the MS attack trial were treated with oral methylprednisolone. In the MS attack trial group, CSF NfH^SMI34 and NfH^SMI35 measured at week 3 and DCSF NfH^SMI34 levels from baseline to week 3 were predictive of clinical outcome at week 8 and 52. In the ON group, no such association was seen. When both groups were combined, baseline CSF NfH^SMI34 and NfH^SMI35 correlated positively with baseline enhancing lesion volume (ELV) (r_s=0.50, p<0.01 and r_s=0.53, p<0.01, respectively). Levels of NfH^SMI35 at baseline and week 3 also strongly correlated with the MBP concentration. This study supports the view that acute inflammation in ON and MS results in axonal pathology and that the latter has a role in determining functional impairment.