The aim of the study was to estimate the rate of conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to investigate variables predicting conversion in a cohort of patients presenting with symptoms suggestive of MS. Patients with a first symptom suggestive of MS in the preceding 6 months and exclusion of other diseases were enrolled in an observational prospective study from December 2004 through June 2007. Conversion from CIS to MS according to both McDonald and Clinically Defined Multiple Sclerosis (CDMS) criteria was prospectively recorded until March 2010. The multivariate Cox proportional hazard model was used to assess the best predictive factors of conversion from CIS to MS. Among 168 patients included in the analysis, 122 converted to MS according to McDonald criteria whereas 81 converted to MS according to CDMS criteria. The 2-year probability of conversion was 57% for McDonald Criteria and 36% for CDMS criteria. Variables at enrolment significantly associated with conversion according to McDonald criteria were age and positivity for Barkhof criteria, and according to Poser's CDMS criteria, age, positivity for Barkhof criteria and no disease modifying therapy. In this large prospective cohort study the conversion rate from CIS to MS in patients presenting with recent symptoms suggestive of MS was within the range of previous observational studies and lower than that reported in the placebo arm of randomized trials. We confirm the prognostic value of MRI in addition to the previous experimental data on the protective role of disease-modifying therapies.