Objectives: To determine (1) whether the serum concentration of 25-hydroxy vitamin D (25(OH)D3) was associated with depression levels in people with chronic spinal cord injury (SCI) and (2) whether any observed association was independent of potential confounders. Design: Cross-sectional study. Setting: Rehabilitation institute. Participants: Patients with chronic SCI (N=100) recruited consecutively. Interventions: Not applicable. Main Outcome Measures: Patients underwent clinical and biochemical evaluations, including assessment of 25(OH)D3 levels and the presence and severity of depressive symptoms, by using the interviewer-assisted self-report Beck Depression Inventory-II (BDI-II). Results: Depression (BDI-II score >= 14) was observed in 15 of 28 women (53.6%) and 18 of 72 men (25.0%) of the study population. They exhibited significantly lower 25(OH)D3 levels, lower functional independence degree in performing activities of daily living, poorer engagement in leisure time physical activity, and higher body mass index. Lower 25(OH)D3 levels were associated with higher BDI-II scores as well as with the occurrence of depression. These associations persisted after adjustment for all significant predictors of the BDI-II score that were selected, as possible confounders, by univariate analysis. In receiver operating characteristic analysis, a 25(OH)D3 level of <9.99ng/mL had the highest accuracy in discriminating patients with depression. Conclusions: In people with chronic SCI, an inverse association exists between serum 25(OH)D3 levels and depressive symptoms, widely independent of potential confounders, especially those, peculiar to this population, that can mediate the effects of depression on vitamin D levels. (C) 2016 by the American Congress of Rehabilitation Medicine