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Objective This study was performed to assess the efficacy of memantine in patients with amnestic mild cognitive impairment (aMCI).Methods Thirty healthy controls and 45 patients diagnosed with aMCI based on the Petersen criteria were classified into 3 groups. Group 1 comprised patients who received a singlememantine dose following examination (n = 25), Group 2 comprised patients who did not receive memantine treatment following examination (n = 20), and Group 3 comprised healthy age-matched volunteers (n = 30). Neuropsychological testing was performed, and the response to memantine was examined at baseline and at 12, 24, and 48 weeks. Single-photon emission computed tomography was performed at baseline and at 48 weeks in patients who received memantine treatment.Results Memantine treatment significantly improved the symptoms of aMCI according to the Wechsler Adult Intelligence Scale-Revised vocabulary subtest, backward digit span, and Blessed Dementia Rating Scale, all of which were recorded for the duration of the study.Conclusion These data indicate that patients with aMCI receiving memantine develop an improved semantic memory compared with no treatment. Further studies including larger patient cohorts are necessary to validate these findings.