Background: Cognitive impairment occurs in almost 70% of multiple sclerosis (MS) patients. The pathophysiology of this impairment is unknown. We have previously shown that loss of vascular compliance along the cerebrovascular tree (i.e., the vascular network extending from superficial pial arteries to deep penetrating arteries) results in suboptimal vasodilation upon neural stimulation, providing insufficient nutrients and oxygen to active neurons (i.e., neural-vascular uncoupling). We hypothesized that this vascular compliance loss might reflect cerebral autoregulation failure contributing to cognitive impairment in MS. Objectives: To assess autoregulatory capacity, by investigating vascular compliance along the cerebrovascular tree, and its relationship to MS-related cognition. Methods: We conducted a prospective study investigating healthy controls (HC), cognitively preserved and -impaired MS patients (defined as those patients with a processing speed 1.5SD higher than HCs mean), and patients with small vessel ischemic disease (SVID) defined as non-specific white matter changes on MRI. Participants were scanned on a Philips 3T MRI scanner using a dual-echo fMRI sequence while they periodically inhaled room-air and hypercapnic gas-mixture (5% CO2 and 95% room air). We assessed vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested-layers. Arterial cerebrovascular reactivity (CVR) was calculated as cerebral blood flow increases per unit increase in end-tidal CO2. Results: Arterial CVR exponentially reduced from the superficial to deep portions of the cerebrovascular tree for HCs (p=0.0014), cognitively-preserved MS patients (p=0.0005), and SVID patients (p=0.0017). No such reductions were observed in cognitively-impaired MS patients (p=0.7244). Arterial CVR in the superficial cortical regions were higher in cognitively preserved MS patients and SVID, compared to HCs. No such differences were observed between HCs and cognitively-impaired MS patients. Conclusions: Vascular compliance increases in the superficial cortical portions observed in SVID and cognitively-preserved MS might represent efficient autoregulation in the setting of deep-white matter ischemia, thereby resulting in efficient neural-vascular coupling and thus, preserved cognition. Failure of this autoregulation might represent reduced vascular compliance along the cerebrovascular tree resulting in neural-vascular uncoupling and cognitive slowing in MS.