Polyserositis is a challenging differential diagnosis. We present a case of severe serositis in a 51-year-old Caucasian woman complicated by pericardial, peritoneal and pleural exudates in the setting of panhypopituitarism and no other obvious etiology. The patient had obtundation, pretibial edema, anemia, hyponatremia, and high levels of CA 125. Low levels of TSH, free T3 and free T4 suggested central hypothyroidism. Decreased levels of morning cortisol, growth hormone, and gonadotropins indicated panhypopituitarism. The patient reported cessation of menses after her last delivery approximately 20 years ago. To our knowledge, this is the first reported case of panhypopituitarism presenting with polyserositis.