Objectives (1) To examine the mediating effects of depressive symptoms on the relations between employment, grief, depression treatment, and participation enfranchisement after spinal cord injury (SCI); and (2) to examine the moderating role of demographic and injury characteristics, including sex, race, marital status, education, and injury level, and completeness on these relations. Design Cross-sectional survey as part of the Project to Improve Symptoms and Mood after SCI (PRISMS). Setting Rehabilitation facilities. Participants Persons with SCI (N=522; average age, 42y; 76% men; 64% white; 64% completed at least a high school education) enrolled from 2007 to 2011. Interventions Not applicable. Main Outcome Measure Participation enfranchisement. Results The final model fit the data relatively well (comparative fix index=.939; Tucker-Lewis Index=.894; root mean square error of approximation=.066; 90% confidence interval,.043-.089), explaining 32% of the variance in participation enfranchisement. Enfranchisement was positively related to employment and negatively related to depression. Grieving the loss of a loved one and the use of an antidepressant or psychotherapy were related to participation enfranchisement; these relations were mediated by depressive symptoms. Multigroup analyses supported the model's invariance across sex, marital status, severity of injury, and level of injury. Conclusions Depression appears to mediate the influence of employment, grief, and depression treatments on participation enfranchisement after SCI. These relations are applicable regardless of sex, marital status, and injury completeness and level. These findings highlight efforts to improve the detection and treatment of depression in SCI rehabilitation programs that may enhance participation. ©2014 by the American Congress of Rehabilitation Medicine.