Summary Background The dexamethasone/corticotropin releasing hormone (Dex/CRH) test has been proposed as a potential tool for identifying endophenotypes relevant to mood disorders. An exaggerated cortisol response to the test during major depressive episodes has been demonstrated for inpatients with melancholic or psychotic features. A diminished hormone response has been observed in chronically depressed outpatients. Methods Following a battery of self-report and interview assessments, 68 adults completed the Dex/CRH test. Thirty-four met structured interview criteria for current major depressive disorder and 34 age- and sex-matched control subjects had no current or lifetime DSM-IV depressive disorder. Effect of diagnosis on cortisol response to the Dex/CRH test was examined in a repeated measures general linear model. Results The matched groups were equivalent with regard to childhood adversity. Cortisol response to the Dex/CRH test among subjects with current MDD was not significantly different from that seen in matched healthy controls. Independent of diagnosis, an exploratory analysis showed a trend-level association between maltreatment history and diminished cortisol response; no interactive effects with depression diagnosis were detected. Conclusions The results do not support the hypothesis that elevated cortisol response to the Dex/CRH test represents a marker for major depressive episodes.