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Background: A large body of evidence suggests that immune system dysregulation is associated with Major Depressive Disorder (MDD) in adults. This study extends this work to adolescent MDD to examine the hypotheses of immune system dysregulation in adolescents with MDD, as manifested by significantly: (i) elevated plasma levels of cytokines (interferon [IFN]-gamma, tumor necrosis factor-alpha, interleukin [IL]-6, IL-1beta, and IL-4); and (ii) Th1/Th2 cytokine imbalance shifted toward Th1 as indexed by increased IFN-gamma/IL-4., Method: Thirty adolescents with MDD (19 females; 13 medication-free/naïve; ages 12-19) of at least 6 weeks duration and a minimum severity score of 40 on the Children's Depression Rating Scale-Revised, and 15 healthy comparisons (8 females), group-matched for age, were enrolled. Plasma cytokines were examined using enzyme-linked immunosorbent assay. Mann-Whitney test was used to compare subjects with MDD and controls., Results: Adolescents with MDD had significantly elevated plasma IFN-gamma levels (3.38+/-11.8 pg/ml versus 0.37+/-0.64 pg/ml; p<0.003), and IFN-gamma/IL-4 ratio (16.6+/-56.5 versus 1.76+/-2.28; p=0.007). A trend for IL-6 to be elevated in the MDD group was also observed (1.52+/-2.88 pg/ml versus 0.49+/-0.90 pg/ml; p=0.09). Importantly, findings remained evident when medicated subjects were excluded., Conclusions: Findings suggest that immune system dysregulation may be associated with adolescent MDD, with an imbalance of Th1/Th2 shifted toward Th1, as documented in adult MDD. Larger studies with medication-free adolescents should follow.