A 58-year-old male presented with persistent severe headache, lethargy, decline libido and no neurological deficits. Besides quadruple anterior pituitary hormonal deficiencies, magnetic resonance imaging (MRI) demonstrated an enlarged ring-enhanced non-homogenous pituitary. Following hormonal replacement, these symptoms improved but empty sella evolved. The challenges of diagnosis and management were discussed. Awareness of the unclear etiology and uncertain clinical course of autoimmune hypophysitis in a man in this age group is essential for prompt and appropriate management.