Previous studies based on case descriptions and neuroradiological findings have suggested central nervous system (CNS) involvement in facioscapulohumeral dystrophy. The aim of this work is to explore the relationship between cognitive/personality pattern and the underlying molecular defect for this muscular dystrophy. We performed a wide-ranging neuropsychological assessment of 34 molecularly confirmed facioscapulohumeral dystrophy patients and 49 control subjects, all of whom also received the Millon-II Multiaxial Clinical Inventory (MCMI-II). Patients and controls show mild learning-level differences in the neuropsychological profile, and only the hysteriform scale is statistically higher in patients than controls. The patients’ intelligence quotient (IQ) is related to the size of the deleted fragment but not to the degree of muscular impairment. The results of this study indicate a cut-off point and two distinct cognitive profiles in facioscapulohumeral dystrophy, depending on the patients’ molecular defect: patients with a fragment size >24 kb show a relatively normal cognitive pattern, whereas those with a fragment size ≤24 kb show a significantly reduced IQ and difficulties with verbal function and visuo-constructive tasks. This work provides more evidence for the involvement of the CNS in facioscapulohumeral dystrophy and suggests that the fragment size should be taken into account in the clinical management of facioscapulohumeral dystrophy as it has a predictive value on the cognitive phenotype.