Objective: To examine the association of neuropathic and nociceptive pain severity and interference with quality of life (QoL) in persons with spinal cord injury (SCI) who underwent a randomized controlled 12-week trial of an antidepressant to treat depression. A secondary objective was to assess the effect of changes in pain on mobility and physical independence. Design: Multivariable ANCOVA models controlling for relevant demographic covariates, treatment condition, and baseline pain and QoL were used. Setting: Six rehabilitation centers. Participants: Of the 133 persons who were randomized into the trial, 108 provided pain severity and interference ratings through follow-up. Interventions: Not applicable. Outcome Measures: The Satisfaction with Life Scale and the physical and mental component summary scores of the 12-Item Short-Form Health Survey (SF-12). Secondary outcome measures included the mobility and physical independence subscales of the Craig Handicap Assessment and Reporting Technique (CHART). Results: Broadly, few associations between pain and QoL were evident. Results revealed relationships between lower baseline nociceptive pain interference and higher satisfaction with life and mental health-related QoL at 12 weeks. Similarly, lower neuropathic pain interference was associated with change in physical independence, but unrelated to mobility. Conclusions: Pain interference over time may be differentially related to QoL outcomes based on the type of pain following SCI, but overall, there were no extensive relationships between pain and QoL in this sample of depressed persons with SCI.