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Background  Amantadine hydrochloride is one of the most frequently prescribed drugs for patients with severe traumatic brain injury in restoring consciousness and accelerating the pace of functional recovery. However, there is a paucity of studies on the effectiveness of amantadine in patients with severe stroke especially large hemisphere infarction (LHI). The present study aimed to investigate whether amantadine treatment is associated with better clinical outcomes in conservatively treated LHI patients.    Methods  We retrospectively collected conservatively treated LHI patients according to inclusion/exclusion criteria. The patients were divided into two groups based on the treatment regimen, whether they did receive amantadine hydrochloride in addition to standard therapy (ST) or not. The primary outcomes were in-hospital death, 3-month mortality, and unfavorable outcome (defined as modified Rankin Scale score of 4 to 6). All outcomes were compared between the two groups before and after propensity score matching (PSM). Multivariate logistic regression was performed to identify the association between early amantadine hydrochloride treatment and clinical outcomes in LHI patients.    Results  Thirty-one LHI patients treated with amantadine combined with ST and 127 patients treated with ST were enrolled. Amantadine group had a shorter prehospital delay (median: 2 vs. 10 h), a higher baseline NIHSS score (21.71 ± 4.76 vs. 17.49 ± 5.84), and a higher rate of dominant hemisphere involvement (67.74% vs. 45.67%). After PSM, amantadine treatment significantly reduced the risk of in-hospital death (7.41% vs. 31.11%,  p =0.019) and 3-month mortality (25.93% vs. 55.56%,  p =0.008). Amantadine treatment yielded a significant decrease in death in-hospital (before PSM: OR 0.143, 95% CI 0.034 to 0.605; after PSM: OR 0.113, 95% CI 0.020 to 0.635) and 3-month mortality (before PSM: OR 0.214, 95% CI 0.077 to 0.598; after PSM: OR 0.176, 95% CI 0.053 to 0.586) in unmatched and matched multivariate analyses.    Conclusion  The results of our study provide initial evidence that early amantadine treatment was associated with a decrease in death in conservatively treated LHI patients. Considering the limitations of observational study, randomized controlled trials with a large sample size may help provide a clearer picture of the utility of amantadine in LHI patients.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12883-021-02444-w.

Early amantadine treatment reduces the risk of death in patients with large hemisphere infarctions:a Chinese hospital-based study