Objectives: This study explores factors associated with psychological wellbeing and distress in people with Multiple Sclerosis (MS). The role of physical symptoms, illness representations and experiential avoidance in predicting psychological distress was assessed. Design: Cross-sectional data was collected from 121 participants with a diagnosis of MS. Path analysis was used to test a hypothetical model of distress in MS that hypothesised that experiential avoidance would mediate the relationships between level of symptoms and distress, and between illness representations and distress. Methods: Participants completed questionnaires assessing level of physical symptoms (EDSS), illness representations (BIPQ), experiential avoidance (AAQ-II), and psychological distress (GHQ-30). Path coefficients, allowing direct and indirect relationships to be evaluated, were obtained from a series of simultaneous multiple regression analyses; one for each endogenous variable (experiential avoidance, distress). Results: Participants results highlighted significant positive associations between all the variables (symptoms, illness representations, experiential avoidance) and distress. Path analysis revealed that experiential avoidance did not mediate the relationships between level of symptoms and distress, nor illness representations and distress. Illness representations were the strongest predictor of psychological distress, while experiential avoidance was the strongest predictor when distress was conceptualised as depression. Conclusions: Overall the study did not suggest that experiential avoidance mediates the relationship between illness representations and psychological distress; instead illness representations alone accounted for most of the variance in psychological distress. Experiential avoidance accounted for most of the depression experienced by participants. These results have a direct impact on how psychological interventions are delivered for people with MS, suggesting that disease factors, and beliefs about the illness, need to be taken account of and incorporated into treatment for presenting problems.