Abstract Introduction: Primary Adrenal Insufficiency (PAI), also known as Addison's disease, is a rare endocrinopathy resulting from the destruction or dysfunction of the adrenal cortex. It has an estimated increasing prevalence between 100 and 140 cases/million and an incidence of 4 cases per million/year. On the other hand, Acute Myeloid Leukemia (AML) is the most common leukemia among adults and accounts for about 80% of all cases. Even though our case is exceptionally rare, it highlights the coexistence of both conditions in the same patient and that PAI can be the presenting symptom of AML. Case Report: A 52-year-old female with a history of lower extremity cellulitis presented for evaluation after experiencing fever, chills, fatigue, night sweats, nausea, and dysphagia. On arrival, she had pharyngeal erythema with cervical lymphadenopathy. Her white blood cell count was 33,000. A CT chest revealed bilateral neck adenopathy and an enlarged left hilar lymph node. Bone marrow flow cytometry results were consistent with AML, CD33 positive with 68% blasts. Induction chemotherapy with gemtuzumab ozogamicin and dexamethasone IV was initiated. Meanwhile, she developed acute abdominal pain. A CT abdomen/pelvis revealed bilateral adrenal symmetric thickening, indicating adrenal dysfunction, a new finding compared to prior imaging. Endocrinology was consulted. Physical examination revealed hyperpigmented palmar creases, fatigue, and nausea, raising suspicion of adrenal insufficiency. Laboratory work showed sodium 134, basal ACTH 10, and morning cortisol levels less than 1 mcg/dl. An ACTH stimulation test confirmed PAI, with ACTH increasing from 26 to 47, cortisol from 9.2 to 11.7, aldosterone from 2 to 15, and high plasma renin activity 2.64. She continued on steroid therapy with monitoring of blood pressure and sodium levels for two weeks. She was eventually discharged with a medication plan and follow-up appointments with endocrinology and hematology/oncology. Discussion: The coexistence of PAI and AML in the same patient is rare. Obscure clinical presentations complicated the diagnosis. Symptoms like fatigue, weakness, and nausea are common in AML patients, but hyperpigmentation of the palmar creases is not. We recommend evaluating adrenal function in acute leukemia patients to avoid adrenal insufficiency crises. If adrenal insufficiency was considered later, early steroid discontinuation could have provoked an adrenal crisis. Monitoring should continue to determine if the concern is permanent or transient. Conclusion: High suspicion and early evaluation of adrenal function in all acute leukemia patients should be considered to avoid adrenal insufficiency as a later complication. Due to the rarity of the disease and non-specific early symptoms, PAI is frequently not considered, leading to delayed diagnosis and increased risk for adrenal crisis. Successful long-term therapy relies on adequate patient education, frequent assessment of basal and stimulated cortisol levels, testing of HPA axis integrity, and various imaging techniques. Citation Format: Maria Toustsoglou, Aliya M. Khan, Mehmet Hepgur, John McDonald, Rubens Sievert. Primary adrenocortical insufficiency as a presenting symptom of acute myeloid leukemia [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C068.