The present study examined the changes of depressive symptoms and salivary cortisol responses in 36 outpatients with major depression. These patients were randomly assigned to receive combination therapy (CT), consisting of antidepressants and body-mind-spirit group psychotherapy, or monotherapy (MT), consisting of antidepressants only. The results indicated that CT and MT had similar effects on reducing depressive symptoms. Nevertheless, the results revealed that cortisol levels at night appeared to have a greater reduction in CT than in MT, indicating a downward trend in CT but an upward trend in MT. Moreover, a steeper diurnal pattern of cortisol—a larger deviation in cortisol levels between 30 and 45 minutes postwaking and evening—was more likely associated with CT than MT. The findings suggest that CT produced a protective effect on outpatients with major depression, preventing the increased night salivary cortisol levels and the flatter diurnal cortisol pattern that tended to occur in MT.