Background: Both fatigue and reduced physical activity are important consequences of multiple sclerosis (MS). However, their mutual association is poorly understood.Objective: The objective of the study was to determine the relation between perceived fatigue and home-based recording of motor activity in patients with MS.Methods: Found associations were checked for confounding by age, Expanded Disability Status Scales (EDSS), disease duration, sub-type of MS, anxiety, and depression. Forty-three ambulatory patients with MS were recruited. Ambulatory physical activity was recorded for 24 hours. Fatigue was assessed with the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS) and the Checklist Individual Strength (CIS20R). Linear regression was applied after which potential confounding factors were introduced in a multivariate regression model.Results: No significant associations between physical activity and fatigue scores were found, except for the MFIS sub-scale 'physical activity' (ßphysical-activity [ßpa] = -0.044; SE = 0.020). The association between physical activity and the FSS score was distorted by age, MS-type, anxiety and depression and the association between physical activity and the MFIS score by age and depression. The inverse association between MFIS sub-scale 'physical activity' and physical activity was significantly strengthened by adjusting for age (ßpa = - 0.052; SE = 0.019), sub-type of MS (ßpa = - 0.048; SE = 0.020), anxiety (ßpa = - 0.070; SE = 0.023) and depression (ßpa = - 0.083; SE = 0.023).Conclusions: In MS, there is no, or at best a weak association between severity of perceived fatigue and physical activity. Depending on the fatigue questionnaire used, patient characteristics such as age, type of MS, depression and anxiety are factors that may affect this relationship. © SAGE Publications 2011.