Abstract Disclosure: M. Velasquez: None. S. Shekhar: None. R.M. Goyal: None. Background: Ectopic ACTH secreting tumors are responsible for almost 10% of all cases of Cushing Syndrome. Tumors associated with this entity are most commonly small cell lung, thymic, and pancreatic neuroendocrine tumors. Few cases of colon adenocarcinoma with paraneoplastic ACTH secretion have been reported. They are associated with poor outcomes. Clinical case: A 57-year-old previously healthy male presented with shortness of breath and hypertension. CTA of the chest revealed metastatic liver lesions. CT abdomen and pelvis confirmed metastatic liver lesions with an apple core colonic mass consistent with a primary malignancy. Liver biopsy showed well-differentiated neuroendocrine tumor; tumor cells were negative for CK20, chromogranin, and CD56 but positive for CK7 and synaptophysin. The Ki-67 index was 30%. He was not evaluated for paraneoplastic hormonal secretion and the colonic mass wasn’t biopsied at that time. Ga-DOTATATE scan was negative for somatostatin uptake. He was started on carboplatin-etoposide + dexamethasone (three doses of 4mg each). Two months later presented with large bowel obstruction. Colonoscopy was performed and histopathology demonstrated colonic adenocarcinoma with focal neuroendocrine differentiation with positive CDX2 and negative CK7 and CK20. Synaptophysin was diffusely positive with sparse chromogranin positivity. ACTH stain of the colonic biopsy was negative. Chemotherapy was switched to FOLFORINOX and dexamethasone (one dose of 12mg). After two weeks of being on this regimen, he developed refractory hypokalemia and metabolic alkalosis and was sent to the emergency department. Vitals signs were within normal limits except for mildly elevated blood pressure. Physical examination remarkable for redness of his truncal skin. He did have changes in his handwriting, 0/3 three-word recall, and reduced short term memory. Primary team performed a morning cortisol that was elevated, and endocrinology was consulted. Two repeated 8AM cortisol level and a serum ACTH were found to be elevated. An 8mg overnight dexamethasone suppression test revealed an increase in cortisol. MRI brain showed no evidence of intracranial abnormalities. Refractory hypokalemia due to ectopic ACTH-dependent Cushing syndrome was diagnosed warranting treatment with ketoconazole. Unfortunately, he developed septic shock which led to his demise. Conclusion: This case illustrates a paradoxical rise in serum cortisol levels after dexamethasone suppression test suggesting the presence of positive feedback effects of exogenous corticosteroids on tumor’s ACTH release/production. Recognition of this syndrome is critical to avoid unnecessary use of exogenous glucocorticoids since they could trigger paraneoplastic Cushing syndrome in these patients. Presentation: Thursday, June 15, 2023