Background: Borderline personality disorder (BPD) is a complex, severe and highly stigmatised psychiatric illness. Several lines of evidence highlight the causal link between chronic stress, glucocorticoid response to stress and glutamatergic overactivity as a key event in the pathophysiology of BPD. Therefore, molecular mechanisms capable of regulating glutamate excitotoxicity represent novel and potentially promising treatment targets. Memantine-HCl is a voltage-dependent N-methyl-d-aspartate (NMDA) receptor ‘channel blocker’ that selectively blocks pathological glutamate overactivity. Objective: The aim of the current study was to determine if memantine can improve BPD symptoms. Method: An 8-week, double-blind, placebo-controlled trial of adjunctive memantine to treatment as usual was conducted. Treatment as usual comprised antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, noradrenergic and specific serotonin antagonists and serotonin noradrenaline reuptake inhibitors), mood stabilisers and antipsychotics, as well as psychotherapy and other psychosocial interventions. Sixteen participants received oral placebo while 17 participants received daily oral memantine 10 mg for 7 days, with subsequent titration to daily oral memantine 20 mg. Eligibility criteria included men and women aged between 16–65 years, with a diagnosis of BPD according to the Diagnostic Interview for Borderline Patients. Primary outcome measures included the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD), assessed fortnightly. Secondary measures included an adverse effect questionnaire administered fortnightly to assess adverse effects known to be related to memantine use. Results: According to intention-to-treat, latent growth curve analyses, a significant change in total score of ZAN-BPD symptom severity was observed in the memantine group at 20 mg/daily across time, compared with placebo (p = 0.02). No adverse effects were significantly more frequent among participants receiving active memantine than among those receiving placebo. Conclusion: Memantine at a 20-mg daily dose is a well tolerated drug that can improve BPD symptomatology and may be a promising novel therapeutic for its treatment. Further studies are needed to explore the efficacy of memantine versus placebo, as well as in comparison with other potential treatments for BPD. ClinicalTrials.gov identifier: NCT02097706.