Background: Multiple Sclerosis has a great impact on psychological functioning of patients and can be associated with various mental health disorders and symptoms. The most prevalent one is depression, which ranges from 15 to 47 %. Methods: The study design is a randomized controlled clinical trial. Eighty-eight patients with Multiple Sclerosis and depressive symptoms will be recruited and randomized to either Mindfulness Based Intervention or an active control group. The latter is designed to control for non-specific elements of the intervention and it comprises psycho-education and relaxation techniques. The primary outcome is the reduction of depressive symptoms as measured via the Beck Depressive Inventory-II. Secondary outcome measures are level of quality of life, anxiety, perceived stress, illness perception, fatigue and quality of interpersonal relationship. Outcomes will be assessed at baseline, after treatment and 6 months after the end of the treatment. Caregivers will participate in groups together with patients. Discussion: As far as we know this trial will be the first randomized controlled trial testing the efficacy of group-based Mindfulness Based Intervention for patients with Multiple Sclerosis with a comparison with an active control group with a specific focus on depressive symptoms. Trial registration: NCT02611401.