A 22-year-old, captive-born, presumed female Hoffmann’s two-toed sloth (Choloepus hoffmanni) presented in respiratory distress with severe dehydration, hypotension, and a palpably distended stomach. During treatment, dysphagia was noted, and oral examination revealed enlarged palatine tonsils and mucosal plaques. Bloodwork showed a low normal sodium:potassium ratio, a decreased baseline cortisol, and a decreased ACTH-response test. All values were compared to a healthy male Hoffmann’s two-toed sloth at the same facility. Despite aggressive medical management and treatment for hypoadrenocorticism, the sloth was found deceased in her hospital enclosure. Necropsy revealed abdominal effusion, multifocal yeast-like plaques throughout the upper gastrointestinal tract, subcutaneous edema, pulmonary effusion, and testes. Histopathology revealed marked adrenal cortical atrophy and intranuclear mucosal inclusions. Advanced molecular techniques were unable to uncover any viral etiologies—it is unknown whether the yeast-like organisms or viral disease confounded the diagnosis of Addison’s disease. This is the first reported case of hypoadrenocorticism in a Hoffman’s two-toed sloth.