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Background: Increased inflammation is reported in Major Depressive Disorder (MDD), which may be more pronounced in suicidal subjects. Vitamin D deficiency may drive this pro-inflammatory state due to vitamin D's anti-inflammatory effects.Methods: We quantified plasma 25-hydroxyvitamin D (25(OH)D) and inflammatory markers interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and other inflammatory indices, neutrophil-to-lymphocyte ratio (NLR) and white blood cell count (WBC) in 48 un-medicated MDD subjects (n = 17 with mild-to-moderate suicidal ideation [SI]) and 54 controls. IL-6 and TNF-α were combined into a composite inflammation score.Results: There were no significant differences in 25(OH)D levels between MDD and controls (p = 0.24) or between MDD with and without SI (p = 0.61). However, 25(OH)D was negatively correlated with all measured inflammatory markers; these correlations were stronger in MDD subjects, and particularly in those with SI. MDD status significantly moderated the relationships between 25(OH)D and NLR (p = 0.03), and 25(OH)D and WBC (p < 0.05), and SI significantly moderated the relationship between 25(OH)D and NLR (p = 0.03).Limitations: The study was cross-sectional, thereby limiting causal inference, and had a small sample size. Only seventeen of the MDD subjects had SI.Conclusion: While 25(OH)D levels did not significantly differ in MDD vs. controls, or in MDD with or without SI, lower 25(OH)D was associated with indices of immune activation in MDD, especially in cases with SI. Although our findings do not address causality, they are consistent with findings that relatively low 25(OH)D levels in MDD are associated with a pro-inflammatory state. [ABSTRACT FROM AUTHOR]