PURPOSE: To evaluate the feasibility of a combined upper limb and breathing exercise for a home-based program and to explore its effect on primary fatigue and quality of life in ambulatory and non-ambulatory individuals with multiple sclerosis (MS) in a short time. METHOD: Nineteen individuals with MS were assigned into semi-controlled pre-post feasibility study based on Expanded Disability Status Scale (EDSS) status and divided into two groups: exercise (five ambulatory, five non- ambulatory ; EDSS 1.0-8.0) and related control with no exercise (four ambulatory, five non- ambulatory ; EDSS 1.0-7.5). Exercise group performed combined upper limb and breathing exercise in a controlled group (2 days/week, 60 min/session) accompanied by independent home exercise (3 days/week, ≥ 20 min/session). Participants underwent measures of fatigue impact (Modified Fatigue Impact Scale (MFIS) and quality of life (RAND Medical outcomes study 36-item short-form health survey (SF-36)) before and after a 4-week period. RESULTS: The MFIS (physical, psychosocial, total) showed statistically significant group-by-time interaction in ambulatory (p = 0.033, d = 1.60 ; p = 0.039, d = 1.59 ; p = 0.033, d = 1.62) and non-ambulatory individuals (p = 0.009, d = 2.42 ; p = 0.018, d = 1.96 ; p = 0.0008, d = 3.92). Physical functioning (SF-36) showed statistically significant group-by-time interaction in ambulatory (p = 0.014, d = 2.14) but no significance in non-ambulatory (p = 0.368, d = 0.68) individuals. Despite the absent statistical significance, there were large intervention effects on MFIS cognitive scores for ambulatory (d = 1.28) and non- ambulatory (d = 1.47), and on other SF-36 scores for ambulatory (general health: d = 1.76 and pain: d = 1.02) and non-ambulatory (physical limitation: d = 1.03 and emotional well-being: d = 0.94) individuals. CONCLUSION: Our 4-week program reduced some aspects of fatigue and improved some aspects of quality of life in a small group of ambulatory and non- ambulatory individuals with MS. Good feasibility and significant positive changes from baseline warrant further exploratory work. TRIAL REGISTRATION: Name of the registry: The Impact of Exercise Training on Living Quality in Multiple Sclerosis. Registration: The study was registered at www.clinicaltrial.gov on July 14, 2017. First participant enrollment: August 28, 2017. URL: 602-01/17-01-147 ; Trial registration ID: NTC03222596.