Major Depressive Disorder (MDD) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and altered cortisol awakening response (CAR), a non-invasive biomarker for HPA axis reactivity. We theorized that the CAR resembles the accumulated effects of depression over time, and may therefore predict depressive symptom severity once patients return home following inpatient treatment. Two studies are reported. In Study 1 (n = 101; 57% female), the CAR was measured at intake and self-ratings of depression severity was assessed six weeks following discharge. Study 2 (n = 127; 58% female) was a replication and extension of Study 1 where a follow-up assessment of self-rated depression severity was added at six months following discharge. In Study 1 the CAR at intake showed a tendency towards a negative association with self-reported depression six weeks after discharge. Study 2 extended this finding within a more severely depressed, larger sample, where a blunted CAR predicted self-reported depressive severity six weeks and six month following discharge. These findings suggest that a blunted CAR can predict mood deterioration post treatment in inpatients diagnosed with severe MDD.