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Purpose: The patients with neurological disorders often report a different quality of life (QoL), which is in part explained by clinical-pathological or psychosocial variables. This study evaluated spirituality in patients with chronic brain pathologies, aiming to clarify its specificity and position to a multidimensional model of QoL., Methods: A hundred and ninety-nine adult patients with epilepsy (E) (n = 88), mild cognitive impairment (MCI) (n = 32), ischemic vascular disorders (n = 29), tumors (n = 28), or multiple sclerosis (MS) (n = 22), and 66 healthy subjects were assessed using the World Health Organization Quality of Life (WHOQoL) 100, Spiritual, Religious and Personal Beliefs (SRPB), Beck Depression Inventory (BDI), and State-Trait Anxiety Inventory (STAI) for the QoL, spirituality, depression, and anxiety. The Multiple Ability Self-Report Questionnaire (MASQ) and neuropsychological tests evaluated the cognitive functions., Results: Factor analysis of the SRPB, STAI, and BDI scores yielded four factors: Personal Meaning, Inner Freedom, Awe and Openness, and Mood. Quality of life and spirituality were very similar between the patient groups. In comparison with the controls, all of the patients showed worse QoL, spirituality, mood, and lexical-memory abilities, and the patients with MCI and brain vascular disorders (BVD) also revealed worse cognitive impairments. Trait anxiety, self-rated health, age, and the SRPB Inner independence and Hope and optimism facets predicted the patients' WHOQoL 100 total score; the spiritual, affective, and socioeconomic variables predicted many QoL domains, but diagnosis only affected the Physical domain. Anxiety, self-rated health, Hope and optimism, and Personal beliefs predicted the controls' WHOQoL 100 total score., Conclusions: Spirituality, as marked by the meaning of self, inner independence, and transcendence, is distinct from mood. It cooperates, together with the affective states, to determine the QoL of the patients with chronic brain pathologies whereas diagnosis has a limited impact. These findings support a multidimensional cross-disease model for the QoL in neurological disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)