Mal de Debarquement Syndrome is a neurological disorder of motion perception, triggered by external motion. This study aimed to determine the importance of psychosocial factors in relation to depression and quality of life in Mal de Debarquement Syndrome. A total of 66 participants with self-reported Mal de Debarquement Syndrome completed quality-of-life, symptom severity, stigma, depression, and illness intrusiveness measurements in this naturalistic correlational study. Mal de Debarquement Syndrome was associated with high levels of depression and illness intrusiveness. Illness intrusiveness mediated between stigma and quality of life; also the level of stigma moderated the effect of illness intrusiveness on quality of life. Targeted interventions aimed at alleviating psychological distress may improve quality of life in Mal de Debarquement Syndrome.