We compared early biophase kinetics of dexamethasone in 33 patients with a major depression who received a DST either by an oral (n = 20) or an intravenous (n = 13) route. After an oral DST, the dexamethasone kinetics between 14 suppressors and 6 nonsuppressors were indistinguishable during the early distribution phase. However, elimination of dexamethasone from the circulation was significantly enhanced in DST nonsuppressors, resulting in an association of decreased plasma dexamethasone with elevated post-DST cortisol levels. Following intravenous DST administration, we identified 5 nonsuppressors and 8 suppressors whose plasma dexamethasone kinetics were indistinguishable, and during the elimination phase, were in the same order of magnitude as those of nonsuppressors after an oral DST. We suggest that the actual plasma concentration at the conventional post-DST sampling times does not reflect the biopotency of the test drug to suppress the pituitary adrenocortical activity. Plasma dexamethasone concentrations after an oral DST that were associated with nonsuppressed cortisol seem to be coherent phenomena of the underlying endocrine disturbance, the precise nature of which deserves further study.