Rationale: We hypothesized that platelet-neutrophil interactions occur as a result of acute carbon monoxide (CO) poisoning and subsequent neutrophil activation triggers events that cause neurological sequelae. Objectives: To identify platelet-neutrophil interactions and neutrophil activation in patients and in animal models, and to establish the association between these intravascular events and changes linked to CO-mediated neurological sequelae in an animal model. Measurements and Main Results: Blood was obtained from 50 consecutive patients. Abnormalities were variable depending upon the admission carboxyhemoglobin level and duration of CO exposure. Platelet-neutrophil aggregates were detected and plasma myeloperoxidase (MPO) concentration was significantly elevated in those with confirmed CO poisoning. Among patients exposed to CO for over 3 hours flow cytometry scans of neutrophils revealed increased surface expression of CD18 and in some groups, MPO on the cell surface. Animal models revealed consistent evidence of platelet-neutrophil aggregates, neutrophil activation and surface MPO, and plasma MPO elevation. MPO was deposited along the brain vascular lining and co-localized with nitrotyrosine. CO poisoning caused abnormalities in the charge pattern of myelin basic protein (MBP), changes linked to adaptive immunological responses responsible for neurological sequelae in this model. Changes did not occur in thrombocytopenic rats, those receiving tirofiban to inhibit platelet-neutrophil interactions, or L-nitroarginine methyl ester to inhibit nitric oxide synthesis. Alterations in MBP did not occur in CO-poisoned knock-out mice lacking MPO. Conclusions: Acute CO poisoning causes intravascular neutrophil activation due to interactions with platelets. MPO liberated by neutrophils mediates perivascular oxidative stress that is linked to immune-mediated neurological sequelae.