Purpose: Multiple sclerosis (MS) patients often report high levels of illness intrusiveness. The direct and indirect effects of disability and psychological symptoms on illness intrusiveness remain largely unknown, despite their pervasiveness. The present study aimed to examine how depression and anxiety can serve as mechanisms through which disability may impact illness intrusiveness in 3 life domains-instrumental activities, intimacy, and relationships and personal development. Method: Participants (N = 72) were adults (M age = 47.86, SD = 11.79), predominantly female (73.6%) and diagnosed relapse-remitting MS (81.9%). The data was used from an archival neuropsychological database. Data on self-report measures were analyzed to examine the relationship between disability and illness intrusiveness, with depression and anxiety as mediators. Mediation models were run for total illness intrusiveness and the subscales. Results: Depression and anxiety were significant mediators through which disability may impact overall illness intrusiveness. When examining life domains, depression was a significant mediator in all domains. Anxiety was only a significant mediator between disability and relationships/personal development. Conclusions: Results suggest that greater disability both directly and indirectly interferes with illness intrusiveness via depression and anxiety. However, life domains are differentially impacted. Thus, this study helps to guide interventions on the best symptoms to target to improve illness intrusiveness and overall quality of life. Impact and ImplicationsDisability is intrusive on the daily lives of MS patients, interfering with patients' participation in valued activities and interests. Depression and anxiety are highly prevalent in MS and can serve as mediators through which disability triggers perceived illness intrusiveness. The influence of depression and anxiety differs based on the life domain. Depression is related to illness intrusiveness across life domains (e.g., work, family, romance, diet, health, etc.), whereas anxiety is only associated with illness intrusiveness in relationships and personal development. Treating psychological symptoms can improve the perception of illness intrusiveness and enhance the overall quality of life for MS patients.