Purpose: To investigate the role of core self-evaluations (CSE) in the relationship between perceived stress and depression in persons with spinal cord injury. Method: Two hundred forty-seven adults with spinal cord injury completed an online survey measuring perceived stress, CSE, and depressive symptoms. Results: A multiple regression analysis revealed CSE to significantly mediate the relationship between perceived stress and depression. A hierarchical regression analysis also confirmed that CSE is a significant moderator of the relationship between perceived stress and depression. The association between perceived stress and depression was significantly stronger for low-CSE individuals and weaker for high-CSE individuals. Conclusion: High CSE appears to buffer the effect of perceived stress on depressive symptoms for persons with spinal cord injury. Rehabilitation interventions should aim to enhance CSE as a means to prevent depression among this population.