© 2016 American Academy of Neurology. Objective: To study the contribution of the symptomatic lesion in establishing multiple sclerosis (MS) diagnosis and prognosis. Methods: We performed an observational study based on a prospective clinically isolated syndrome (CIS) cohort of 1,107 patients recruited for clinical and brain MRI follow-up from 1995 to 2014. Eligible patients (n 954) were divided into 4 groups according to baseline MRI: patients with a normal MRI (n 290); patients with a single asymptomatic lesion (n 18); patients with a single cord/brainstem symptomatic lesion (n 35); and patients with more than 1 lesion (n 611). For each group, we studied the risk of second attack, with 2005 McDonald MS and Expanded Disability Status Scale 3.0, using univariable and multivariable regression models adjusted by age, sex, oligoclonal bands, and disease-modifying treatments. We tested the diagnostic performance of a modified dissemination in space (DIS) criterion that includes symptomatic lesions in the total count and compared it to the DIS criteria (at least 1 asymptomatic lesion in at least 2 of the 4 MS characteristic MS locations) for all patients and for the subgroup of patients with brainstem or spinal cord topography. Results: Patients with a cord/brainstem single symptomatic lesion have a higher risk of second attack and disability accumulation than patients with 0 lesions but have a similar risk compared to patients with 1 asymptomatic lesion. Diagnostic properties are reasonably maintained when the symptomatic lesion qualifies for DIS. Conclusions: Despite the recommendations of the 2010 McDonald criteria, symptomatic lesions should be taken into account when considering the diagnosis and prognosis of patients with CIS.