Objective: To investigate the use of coping styles and the relationships linking coping to emotional distress and quality of life in patients with acquired brain injury and multiple sclerosis. Method: Cross-sectional cohort study of 143 patients with acquired brain injury and 310 patients with multiple sclerosis in the chronic stage. Quality of life was measured with the Life Satisfaction Questionnaire (LiSat-9), coping styles with the Coping Inventory for Stressful Situations (CISS-T, task-oriented; CISS-E, emotion-oriented; CISS-A, avoidance), emotional distress with the Hospital Anxiety and Depression Scale (HADS). Results: Coping styles did not differ between types of multiple sclerosis and varied only little with regard to severity of disease. In both patient groups, task-oriented coping was most used followed by avoidance and emotion-oriented coping. Patients with multiple sclerosis used all styles to a greater extent. In acquired brain injury, lower CISS-E and lower HADS scores were associated with higher LiSat-9 scores. CISS-E had a direct effect on LiSat-9 and an indirect effect via HADS. In multiple sclerosis, next to lower CISS-E and lower HADS scores, higher CISS-A scores were also associated with higher LiSat-9 scores. CISS-E had an indirect effect and CISS-A had a direct and indirect effect on LiSat-9. Conclusion: In both patient groups, coping patterns are similar, and emotion-oriented coping negatively influences quality of life. Additionally, in multiple sclerosis, seeking emotional support and distraction (CISS-A) was positively associated with quality of life. Interventions to improve adaptive coping could be organized within a neurorehabilitation setting for both patient groups together.