Major depressive disorder (MDD) in adolescents demonstrates resistance to tricyclic antidepressants and absence of hypercortisolemia. The efficacy of serotonin reuptake inhibitors (SRIs) is uncertain, and response predictors are unavailable. Abnormal fast feedback and negative feedback of the hypothalamic-pituitary-adrenal axis implicates a dampened limbic-hippocampal glucocorticoid type II receptor (GCII). We hypothesized that lymphocyte GCII is altered in adolescent MDD and could serve as a marker for response to SRIs. In an open-label study, adolescents (n = 20) meeting DSM-III-R criteria for MDD showed baseline lymphocyte GCII sites per cell (sites/cell) values of 793 +/- 106 versus 2,563 +/- 499 (+/- SEM) for matched controls (n = 18) (t = 3.5; df = 36; p < .001). GCII was bimodally distributed, with SRI responders differing from nonresponders (t = 3.9; df = 14; p < .001). GCII accurately classified 90 percent of sertraline responders and 80 percent of nonresponders. Only SRI responders showed GCII sites/cell upregulated after 6 weeks of treatment (t = 2.1, df = 10; p < .05).