Primary adrenal insufficiency during immunotherapy is rare and does not warrant systematic screening during treatment. It should be suspected in case of typical clinical and biological presentation, but also in case of subclinical presentation with impaired general health status and/or hyponatremia. Diagnosis is based on low cortisol levels, measured at any time in case of emergency or else at 8 am, associated to elevated ACTH to rule out pituitary origin. Secondarily, anti-21-hydroxylase antibody assay may be performed, with screening for mineralocorticoid deficiency. Imaging is recommended, although not urgent, to screen for “adrenalitis” or adrenal atrophy and rule out differential diagnosis of adrenal metastasis. Primary adrenal insufficiency during immunotherapy is a medical emergency requiring hydrocortisone replacement adapted to the clinical and biological context. Management by an endocrinologist is essential, in order to adapt hydrocortisone and fludrocortisone replacement therapy and to educate both patient and oncologist in hydrocortisone dose adaptation. Current data suggest that treatment needs to be life-long, even after termination of immunotherapy. The present article does not deal with secondary adrenal insufficiency, which is included in the section on “Pituitary toxicity”.