Cognitive impairment (CI) is common and debilitating in patients with multiple sclerosis. However, little is known about how different disease courses affect CI, impeding prognosis and disease management. Here, we contrasted the magnitude and profile of CI measured with standardized neuropsychological tests in patients with primary progressive multiple sclerosis (PPMS) against relapsing-remitting multiple sclerosis (RRMS) while considering potentially confounding demographic and clinical differences. Systematic literature review and meta-analysis was performed finding 47 eligible studies (N = 4460 patients). Effect-sizes for 12 cognitive domains were calculated as Hedges’ g. Results indicated more severe CI overall (g = −0.37, p < .001) and in each single cognitive domain (g = −0.28 to −0.65, p < .001) in patients with PPMS despite comparable degrees of fatigue and depression. Moderator analyses revealed that these differences were not fully attributable to clinical heterogeneity between disease courses (e.g., age, disability). Particularly verbal learning and memory differentiated PPMS and RRMS independent from demographic differences. Results imply that, previously under-recognized, PPMS patients display severe degrees of CI and need more specialized disease management than RRMS patients.