Background: Multiple system disorder is a life-threatening with high mortality and morbidity associated with the number of organs dysfunction, and excess utilization of health care resources. Multiple system disorder affects the daily lives of many patients confronted by changes in mental health status, lifestyle, and  leading to impaired self-efficacy to manage medical condition. Aim of the study: the study aimed to assess depression and self-efficacy among patients with multiple system disorder. Design: A descriptive design was utilized in carrying out this study. Settings: The study was conducted at cardiovascular outpatient clinics affiliated to Ain Shams University Hospital. Study subjects: A purposive sample composed of 100 patients with multiple system disorder, the study duration was six month. Data collection tools: Patient Interview Questionnaire, Beck Depression Inventory and Self-Efficacy for Managing Chronic Disease Scale. Results: Revealed that less than half of studied patients had moderate depression and more than half of studied patients had high self-efficacy. Also, there was a negative correlation between self-efficacy and levels of depression. Conclusion: Although patients with multiple system disorder suggested from depression, they had high level of self-efficacy. Recommendations: Health educational program to provide knowledge with disease process to enhance their life style. Psychosocial counselling to facilitate dealing with depression,   improve mental health and self-efficacy.