Background Symptoms of fatigue have been shown to be associated with heightened levels of disability in patients suffering from a wide range of debilitating health and mental health conditions. The role of fatigue as a determinant of work disability in individuals with work-related musculoskeletal disorders (WRMD) has received little attention. The present study examined the role of fatigue as a determinant of work-disability in individuals with WRMDs. Methods Participants included 117 individuals with WRMDs who completed measures of pain severity, fatigue, depression and disability before and after participating in a behavioral activation rehabilitation intervention. Results Cross-sectional analyses on pre-treatment measures revealed that fatigue contributed significant variance to the prediction of self-reported disability, beyond the variance accounted for by pain severity and depression. Prospective analyses revealed that reductions in fatigue through the course of treatment predicted occupational re-engagement following termination of the intervention. Conclusions The results of the present study suggest fatigue contributes to occupational disability, independent of the effects of pain and depression. The findings also suggest that meaningful reductions in fatigue might be achieved through psychosocial interventions that promote gradual re-integration into discontinued activities, increase participants' exposure to success and achievement experiences, and reduce the severity of depressive symptoms. Behavioural activation interventions such as the one used in the present study might contribute to more positive occupational outcomes in work-disabled individuals who report high levels of fatigue.