Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease with high morbidity and mortality rates. Within 24 hours after aSAH, monocytes are recruited and enter the subarachnoid space, where they mature into macrophages, increasing the inflammatory response and contributing, along with other factors, to delayed neurological dysfunction and poor outcomes. High-density lipoproteins (HDL) are lipid-protein complexes that exert anti-inflammatory effects but under pathological conditions undergo structural alterations that have been associated with loss of functionality. Plasma HDL were isolated from patients with aSAH and analyzed for their anti-inflammatory activity and protein composition. HDL isolated from patients lost the ability to prevent VCAM-1 expression in endothelial cells (HUVEC) and subsequent adhesion of THP-1 monocytes to the endothelium. Proteomic analysis showed that HDL particles from patients had an altered composition compared to those of healthy subjects. We confirmed by western blot that low levels of apolipoprotein A4 (APOA4) and high of serum amyloid A1 (SAA1) in HDL were associated with the lack of anti-inflammatory function observed in aSAH. Our results indicate that the study of HDL in the pathophysiology of aSAH is needed, and functional HDL supplementation could be considered a novel therapeutic approach to the treatment of the inflammatory response after aSAH.