Objective: People with multiple sclerosis often suffer from distress, reduced societal participation and low quality of life. Evidence-based psychological treatment options for multiple sclerosis are limited. The aim of this study was to investigate the effectiveness of Acceptance and Commitment Therapy on participation and quality of life for people with multiple sclerosis. Methods: We performed a non-concurrent multiple baselines design study. Six female patients with multiple sclerosis participated. Randomization was implemented by assigning participants randomly to a baseline (waiting) period of three, six or nine weeks. We measured quality of life, and participation on a daily basis, and acceptance and cognitive defusion on a weekly basis. Statistical analyses were performed using randomization tests. Results: After Acceptance and Commitment Therapy, five participants showed statistically significant increases in quality of life and three participants showed statistically significant improvements in participation. Acceptance increased in two patients, and cognitive defusion improved in one patient. Conclusion: Acceptance and Commitment Therapy seems promising for improving the quality of life and participation in people with multiple sclerosis. Mechanisms underlying improvement are not clear yet. Further large-scale controlled studies with more representative samples and a longer follow-up period are justified.