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Background/Objective. To explore the effectiveness of a specific working memory (WM) training program in MS patients and healthy controls (HC). Method. 29 MS patients and 29 matched HC were enrolled in the study. MS and HC were randomly split into two groups: nontraining groups (15HC/14 MS) and training groups (14 HC/15 MS). Training groups underwent adaptive n-back training (60 min/day; 4 days). Functional magnetic resonance imaging (fMRI) was used to monitor brain activity during n-back performance (conditions: 0-back, 2-back, and 3-back) at 3 time points: (1) baseline, (2) post-training (+7days), and (3) follow-up (+35days). Results. In post-training and follow-up fMRI sessions, trained groups (HC and MS patients) exhibited significant reaction time (RT) reductions and increases in Correct Responses (CRs) during 2-back and 3-back performance. This improvement of task performance was accompanied by a decrease in brain activation in the WM frontoparietal network. The two effects were significantly correlated. Conclusions. After WM training, both cognitively preserved MS patients and HC participants showed task performance improvement made possible by neuroplastic processes that enhanced neural efficiency.