The human endogenous retroviruses (HERV)-W family contains an extracellular particle detected in multiple sclerosis (MS) patients and designated as MS-associated retrovirus (MSRV). Through nested RT-PCR assays specific for pol MSRV gene, we preliminary reported that its presence in the cerebrospinal fluid (CSF) of early MS patients could be indicative of a poor prognosis upon a three-year follow-up. In the present clinical study, we enlarged our blind observation up to six years. At study entry, 10 MS patients were MSRV+ and eight were MSRV- in the CSF, both groups having a similar mean age and Expanded Disability Status Scale (EDSS) score. After six year follow-up, the mean EDSS significantly differed between the MSRV+ and MSRV- cohorts (4.3 versus 2.2; P = 0.004), as did the annual relapse rate (0.5 in the MSRV+ versus 0.3 in the MSRV-; P = 0.01). Finally, two MSRV+ patients entered the progressive phase, whilst none of the MSRV- group entered this phase, and 9/10 MSRV+ versus 2/8 MSRV patients were treated with immunomodulatory or immunosuppressive drugs (P = 0.009). In conclusion, we found that the presence of MSRV virions in the CSF at the onset of MS is associated, not only with disability accumulation, but also with a higher rate of clinical re-exacerbations. With the known potential pathogenic effects of MSRV given in the literature, further investigations on MSRV are warranted.