INTRODUCTION: Treatment-resistant depression (TRD) remains a challenge, necessitating novel interventions that address associated cognitive deficits. The glutamatergic modulator ketamine exerts rapid antidepressant effects, prompting investigators to assess its impact on cognitive function, specifically working memory. This study explored ketamine's influence on working memory and magnetoencephalography (MEG) patterns during a working memory task in individuals with TRD. OBJECTIVES: To examine the effects of ketamine on working memory, attention, and concentration, and to study MEG patterns during a working memory task in individuals with TRD. METHODS: Twenty-one individuals with TRD (14 with bipolar disorder, 7 with major depressive disorder) received ketamine and placebo infusions in a crossover trial. Behavioral and MEG data were collected at baseline and 6 to 9 h after ketamine and placebo (normal saline) infusion. Working memory, attention, and concentration were assessed with the N-back task. RESULTS: Ketamine significantly improved depressive symptoms but had no effect on cognitive performance. MEG revealed increased gamma power in the parieto-occipital junction coupled with decreased gamma power in the posterior superior temporal sulcus and inferior frontal gyrus after ketamine administration compared to placebo. CONCLUSIONS: Despite robust antidepressant effects, ketamine did not affect working memory, attention, or concentration. However, distinct gamma power changes in brain regions linked to attention and working memory highlight the need to further explore the neurobiological mechanisms underlying ketamine's cognitive effects in TRD. Future research with larger samples, broader cognitive batteries, and repeated ketamine infusions are needed to fully elucidate ketamine's cognitive effects in individuals with TRD.