Objective: In order to unravel the working mechanisms that underlie the effectiveness of a behavioural intervention promoting physical activity in persons with subacute spinal cord injury, the aim of this study was to assess the mediating effects of physical and psychosocial factors on the intervention effect on physical activity. Design: Randomized controlled trial. Setting: Four rehabilitation centres in the Netherlands. Subjects: Thirty-nine persons with subacute spinal cord injury. Intervention: Behavioural intervention promoting an active lifestyle, based on motivational interviewing. The intervention involved a total of 13 individual sessions beginning 2 months before and ending 6 months after discharge from initial inpatient rehabilitation. Main measures: The potential mediating effects of fatigue, pain, depression, illness cognition, exercise self-efficacy, coping and social support on the effect of the behavioural intervention on objectively measured physical activity (B = 0.35 h, p < 0.01) were studied. Measurements were performed at baseline, discharge, 6 months and 1 year after discharge. Results: No single factor was found that strongly mediated the effect of the behavioural intervention on physical activity; however, multiple factors could partly explain the effect. Mediating effects greater than 10% were found for proactive coping (17.6%), exercise self-efficacy (15.9%), pain disability (15.3%) and helplessness (12.5%). Discussion: Proactive coping (the ability to anticipate and deal with potential threats before they occur), exercise selfefficacy (self-confidence with respect to performing exercise and daily physical activities), pain disability (interference by pain of daily activities) and helplessness (emphasizing the aversive meaning of the disease) are important concepts in interventions promoting physical activity in persons with subacute spinal cord injury.