OBJECTIVE:To examine whether cognitive and physical fatigue are differentially associated with problems in self-care, mobility, relationships, participation, psychological well-being, and quality of life in people with multiple sclerosis. METHODS:A cross-sectional study involving seventy-four community-dwelling people with MS was undertaken. Between-groups analysis was used to compare ratings on the Perceived Impact of Problem Profile (PIPP) in a range of functional domains and the SF-36 quality of life measure, across median-split groups based on level of both physical and cognitive fatigue using the Modified Fatigue Impact Scale. RESULTS:The impact of poor psychological well-being (p = .005), and associated distress (p = .008) on PIPP was greater in the 'high-level' cognitive fatigue group than the 'low-level' cognitive fatigue group. By contrast, the 'high-level' and 'low-level' physical fatigue groups differed significantly in their self-reported impact of problems in the areas of mobility (p = .002), relationships (p = .014), participation (p = .001), and psychological well-being (p = .004). Overall mental quality of life was significantly lower (p < .001) in those high in cognitive fatigue comparative to the low-level group, and overall physical quality of life was significantly lower (p = .002) in people with multiple sclerosis high in physical fatigue as opposed to low. CONCLUSION:Cognitive and physical fatigue were associated with distinct problems in daily functioning, which impact differentially on role fulfilment and quality of life in multiple sclerosis. Therefore, these two types of fatigue should be considered distinct domains of the fatigue experience in MS.