Diagnosing isolated ACTH deficiency can be a challenging task for a clinician due to its non-specific symptoms, such as a decreased appetite, general fatigue, and psychological dysfunction. This report is on two patients with isolated ACTH deficiency who presented with extreme appetite loss and were referred for psychiatric evaluation with a suspected diagnosis of depression. 【CaseⅠ】A business executive in his late sixties showed severe appetite loss and vomiting in May of the year X. His business had started to experience difficulty two months earlier. A medical workup of the digestive system and a brain MRI revealed no abnormality. Subsequently, the patient was referred for a psychiatric examination with suspected depression in August. Psychiatric pharmacotherapy improved his appetite only temporarily,and he was admitted as a psychiatric inpatient. A more thorough evaluation led to a diagnosis of isolated ACTH deficiency on the basis of abnormally low levels of ACTH and cortisol. The patient’s symptoms improved with hydrocortisone supplementation. 【CaseⅡ】A factory worker in his late fifties started to experience appetite loss,nausea/vomiting, and decreased energy in May of the year Y,without any apparent cause. Medical evaluations by a family physician, a digestive system specialist, and a neurologist, including a brain CT,were unremarkable. Depression was suspected and the patient was referred to the authors’psychiatric clinic in July of the same year. Upon examination, the patient presented with depressive symptoms such as a depressed mood, decreased energy, middle insomnia,and loss of interest. Blood tests and a hormonal workup revealed abnormally low ACTH and cortisol levels. The patient was admitted as an inpatient of the endocrinology department, and a diagnosis of isolated ACTH deficiency was made. Hydrocortisone supplementation improved his symptoms. In both cases, anti-pituitary antibody was negative and there were no findings of an empty sella or swelling of the pituitary gland. Therefore, isolated ACTH deficiency was a more likely diagnosis than lymphocytic adenohypophysitis. It is important to diagnose this condition as early as possible since it is treatable with hydrocortisone supplementation with a favorable prognosis. Screening for ACTH and cortisol levels should be considered when symptoms of suspected depression include severe general fatigue and appetite loss with vomiting.