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Introduction Multiple sclerosis (MS) usually presents at onset with a clinically isolated syndrome (CIS). According to 2010 McDonald criteria, a diagnosis of MS can be made if CIS patients satisfy clinical/MRI criteria of both dissemination in time (DIT) and space (DIS). Objective The aim of this study was to analyze the follow-up data and possible prognostic factors of CIS patients satisfying DIS MRI criteria. Patients and methods We performed a retrospective, multicenter study across 2 Italian centers. Clinical, MRI, and laboratory assessments were performed according to real-life clinical workup. Results Out of the 137 enrolled patients, during a median follow-up time of 3.1 years, 116 (84.7%) converted to MS with the large majority (78.4%) of the converters developing MS within 1 year. In multivariate analysis, baseline predictors of an earlier conversion were a cerebellar/brainstem CIS (HR 2.00, 95% CI: 1.3–3.0, p = 0.001) and the presence of all the Barkhof-Tintore MRI criteria (HR 1.67, 95% CI: 1.1–2.6, p = 0.028). Conclusions Patients with CIS and DIS are at very high risk of an early conversion to MS. The onset with cerebellar/brainstem symptoms and the evidence of a higher MRI lesion load at baseline are the strongest independent predictors of an early conversion to MS.