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The aim of this study was to assess clinical response to a high-dose intravenous (IV) amantadine given for 5 consecutive days in patients with multiple system atrophy parkinsonism (MSA-P).Subjects with a diagnosis of MSA-P treated with IV amantadine were included. Patients' disease severity before and after therapy was evaluated using the Unified Multiple System Atrophy Rating Scale (UMSARS).Fourteen subjects (8 females) were included. In 10 subjects (71.4%), clinical improvement was noted. The UMSARS score after treatment decreased by 2 points (median [interquartile range, 0–3]) when compared with UMSARS score at baseline (P = 0.0020). Upon examining the walking parameter, a trend of improvement was shown (P = 0.0625) (range, 0–1 points). Neither specific demographic parameters nor occurrence of adverse effects was found to be a predictive factor for improvement. Adverse events were mild and transient except for one patient who experienced acute psychosis prompting treatment cessation, upon which psychosis resolved.Our preliminary data show that IV amantadine may be a safe and effective therapy in MSA-P. A double-blind placebo-controlled trial is needed to establish the true benefit of amantadine therapy.