Opportunistic infection is a well recognised complication of severe hypercortisolaemia. Pneumocystis pneumonia (PCP) has been infrequently reported in Cushing’s syndrome (CS); however during the last decade, an association between the development of PCP after reduction of cortisol levels has been observed. We report a case of fatal PCP in a 51-year-old female with ectopic Cushing’s syndrome secondary to a poorly differentiated, triple negative, invasive breast carcinoma with neuroendocrine features. On presentation the patient had severe metabolic alkalosis and hypokalaemia. 24-hour urinary free cortisol was measured at 40 times the upper limit of normal. Imaging revealed abdominal lymphadenopathy but no other metastases. There was a high intravenous potassium requirement which improved on initiation of spironolactone and ketoconazole; commenced the day following chemotherapy, with a remarkable reduction in urinary cortisol levels. Febrile neutropenia with cough developed 12 days later and despite empiric anti-microbial therapy (including trimethoprim-sulfamethoxazole), there was rapid, severe type one respiratory failure requiring intubation. Bronchoalveolar lavage confirmed Pneumocystis jirovecii infection. Despite maximal measures, gas-exchange progressively deteriorated and all treatment was withdrawn after 4 days. We discovered and reviewed 12 cases in the literature detailing PCP development in CS. All cases had very high endogenous cortisol levels and developed infection only after cortisol-lowering therapy was initiated. A very high mortality rate was observed. The proposed aetiology is that some patients have asymptomatic carriage of Pneumocystis and following endogenous cortisol level lowering, there is reconstitution of the immune system with subsequent vigorous inflammatory response, precipitating PCP. There are no well-established guidelines on opportunistic infection prophylaxis in patients with CS. Based on our experience and review of the literature, prior to commencing cortisol-lowering therapy in patients with significant hypercortisolaemia, we suggest consideration of prophylactic- or treatment-dose PCP therapy depending on Pneumocystis colonisation status, in addition to adjunctive glucocorticoids regardless of cortisol levels.