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Introduction: ICU clinicians must recognizeImmune Checkpoint Inhibitor (ICI) induced hypophysitis as a reversible cause of shock, altered mentation, and FUO in patients receiving immunotherapy. Early endocrine evaluation and empiric corticosteroids can be lifesaving and prevent unnecessary antimicrobial use and prolonged ICU stays. Description: 61-year-old male with left upper lobe squamous cell carcinoma receiving nivolumab presented with progressive weight loss and loss of appetite despite malignancy being in remission. He was found to have high-grade fevers, altered mental status, and progressive hypotension requiring norepinephrine. Patient had no leukocytosis or electrolyte abnormalities. CT of chest/abdomen/pelvis and lumbar puncture were unrevealing. Blood and urine cultures remained negative. Despite broad-spectrum antimicrobials and fluid resuscitation, the patient remained hypotensive and encephalopathic, requiring intubation. Given persistent shock with no clear infectious source, adrenal insufficiency was suspected. AM Cortisol was 1.45 μg/dL, and ACTH was inappropriately low < 1.5. Thyroid function tests were profoundly low with TSH < 0.008, T4 1.45 and free T3 < 0.57, consistent with central hypothyroidism. CT and MRI of the brain were not remarkable for other acute intracranial abnormalities. Stress-dose hydrocortisone (100 mg IV q8h) was initiated. Within 24 hours, the patient defervesced, mental status improved, and vasopressors were weaned. A diagnosis of nivolumab-induced hypophysitis with secondary adrenal crisis was confirmed. Maintenance steroid taper and endocrine follow-up were arranged on discharge. Discussion: This case illustrates the critical importance of maintaining a high index of suspicion for ICI-induced endocrinopathies in ICU patients. Hypophysitis may mimic sepsis and lead to delayed diagnosis, particularly when initial infectious and neurologic workups are unrevealing. Central adrenal insufficiency is the most life-threatening manifestation and requires prompt treatment with stress-dose glucocorticoids. Recognition is challenging due to the nonspecific presentation all of which can be attributed to critical illness. Pituitary MRI may support diagnosis but should not delay empiric steroids when hypophysitis is suspected in a hemodynamically unstable patient.