BACKGROUND: Today, no specific test for the diagnosis of multiple sclerosis (MS) is available due to the lack of characteristic symptoms at beginning. This circumstance also complicates estimation of disease progression. Recent findings provided evidence for early, non-lesional cerebellar damage in patients with (clinically definite) relapsing-remitting MS. OBJECTIVE: To investigate if microstructural cerebellar alterations can also serve as early structural biomarker for disease progression and conversion from clinically isolated syndrome (CIS) to MS. METHODS: 46 patients diagnosed with CIS and 26 age-matched healthy controls were admitted to high-resolution MRI including diffusion tensor imaging (DTI) to examine atrophy and microstructural integrity of the cerebellum. Microstructural integrity of cerebellar white matter was assessed by fractional anisotropy (FA) as derived from DTI. RESULTS: Although all 46 patients of our CIS cohort showed no cerebellar lesions in structural MRI (T1w, T2w, FLAIR), their mean cerebellar FA was already reduced compared to healthy controls. Significant FA reduction at follow-up DTI 6 months after baseline examination was observed. In 16 patients that converted to MS, we found a correlation between initial cerebellar FA and conversion latency (R=0.71, p < 0.002). Initial cerebellar FA under FAcrit=0.352 predicted conversion into relapsing-remitting MS within 24 months (FAcrit: mean cerebellar FA of patients with early MS, determined in another study). CONCLUSION: DTI seems to reflect early tissue injury in beginning MS, when atrophy and lesions are not yet detectable. Decreased cerebellar FA in patients with CIS might indicate an active and unstable disease stage, Resulting in a shorter conversion time into MS.