Objectives: The aim of this study was to evaluate a short-term non-specific home-based 6-week cognitive training for its effect on neuropsychological deficits and depression. Subjects and Methods: Cognitive and affective abilities of patients with MS were compared with healthy controls using an identical neuropsychological test battery. Re-testing was performed after 6 weeks of cognitive home-based training. Results: Patients already showed cognitive deficits at baseline. Cognitive training resulted in a significant improvement in several skills, in particular with respect to visuoconstructive and figural long-term memory. In addition, prior depressed mood and quality of life improved in MS patients during the training period and remained up to 6 months. Conclusions: Our study corroborated the early appearance of neuropsychological deficits in MS. Mental training, although unspecific, lead to improvements with respect to attention and memory functions in patients, and to some degree in control subjects, which may last for more than 6 months.