This study has been carried out to examine (i) transcortin or corticosteroid binding globulin (CBG), the major glucocorticoid transport protein, in major depressed versus minor depressed and normal subjects; and (ii) the relationships between CBG and basal and postdexamethasone cortisol or adrenocorticotropic hormone (ACTH) values. Serum CBG was significantly lower in major depressed than in minor depressed subjects and normal controls. The significant decrease in serum CBG was observed in major depressed women but not in major depressed men. In depressed subjects, there was a significant and negative relationship between serum CBG and severity of illness. There were significant positive relationships between serum CBG and basal 8:00 a.m. plasma cortisol in normal volunteers (r = 0.87, P < 10(-4)) and depressed subjects (r = 0.40, P = 0.0002). There was no significant relationship between serum CBG and 24-h urinary cortisol. In depressed patients, there was a positive relationship between serum CBG and postdexamethasone cortisol (r = 0.31, P = 0.003). It is concluded that, in depression, serum CBG levels should be taken into consideration for the interpretation of baseline and postdexamethasone plasma total cortisol levels.