Objective: To investigate the prevalence and clinical relevance regarding disability progression in multiple sclerosis patients with a dissociation in clinical and radiological disease expression. Methods: We prospectively selected patients with early relapsing–remitting multiple sclerosis (MS) or a clinically isolated syndrome (CIS) from the Amsterdam MS cohort. Patients underwent clinical examination at baseline, after 2 years, 6 years and a subset also after 11 years, including the Expanded Disability Status Scale (EDSS), 25-foot walk test (25-FWT) and 9-hole peg test (9-HPT). Brain and spinal cord MRI scans were obtained at baseline and after 2 years. Two years after baseline, patients with dissociation in their clinical and radiological disease progression were identified as: (1) patients with high clinical disease activity (defined by relapses) and low radiological disease activity (defined by white-matter lesions on T2-weighted imaging); or (2) patients with low clinical disease activity and high radiological disease activity. Binary logistic regression analyses were performed to predict disability progression after 6 and 11 years of follow-up. Patients with low clinical and low radiological disease activity were used as the reference group. Results: The prevalence of clinico-radiological dissociation was low (6.4% had high clinical and low radiological disease activity and 5.1% had a combination of low clinical and high radiological disease activity) compared to 88.5% of patients without a dissociation. Patients with a dissociation of clinical and radiological disease activity did not show a statistically significant difference in risk of disability progression after 6 and 11 years. Conclusions: A clinico-radiological dissociation is rather a rare phenomenon in MS patients. The clinical relevance of such a dissociation regarding the prediction of disability progression is questionable.