Key Clinical MessageIn MS patients, especially those frail or malnourished, combining home-based exercise twice weekly with essential amino acids and vitamin D may improve body composition, strength, and physical performance, enabling long-term functional improvements. Multiple sclerosis (MS) is associated with reduced bone and muscle strength and function. We aimed to investigate the effectiveness of a 24-week intervention in a 57-year-old frail female with MS. The participant completed a 2x/week exercise intervention and ingested 2x/day a supplement containing 7.5 g essential amino acids and 500 IU cholecalciferol. Body composition, 6-m gait speed (GS), handgrip strength (HGS), 30-sec arm-curl test (30ACT), 6-min walking test (6MWT), 30-sec chair-stand test (30CST), and plasma concentrations of 25-hydroxyvitamin D-3 [25(OH)D-3], insulin-like growth factor 1 (IGF-1), and amino acids were assessed at baseline, and at Weeks 12 and 24. Plasma 25(OH)D-3 increased from 23.2 to 41.3 ng/mL and IGF-1 from 131.6 to 140.7 ng/mL from baseline to post-intervention. BMI, total lean tissue mass (LTM), fat mass, bone mineral content, and the sum of 17 amino acids increased by 3.8, 1.0, 3.5, 0.2, and 19%, respectively, at Week 24. There were clinically significant increases in regional LTM (6.9% arms and 6.3% legs) and large increases in GS (67.3%), dominant HGS (31.5%), non-dominant HGS (11.8%), dominant 30ACT (100%), non-dominant 30ACT (116.7%), 6MWT (125.6%), and 30CST (44.4%). The current intervention was effective in improving components of physical fitness and body composition in a female with MS.