Background: Cortisol is a physiological stress hormone and response of cortisol to high altitude exposure is dynamic influenced both by duration of exposure and exertion. It steadily increases following high altitude exposure or exercise and gradually plateaus on prolonged stay in high altitude areas. The variations in physiological cortisol response may have a pathological influence on High Altitude Pulmonary Oedema (HAPO) development. This study was carried out to test whether individuals who developed HAPO had a poor physiological stress cortisol response on exposure to high altitude. Methods: Thirty patients admitted with HAPO along with thirty healthy controls who rapidly ascended to a high altitude were recruited in the study. The serum cortisol levels was estimated at the time of admission with HAPO and from healthy controls on 2nd or 3rd day of high altitude induction. The subjects (both patients and controls) were also subjected to ACTH stimulation test to determine adequacy of stress cortisol response as results of initial cortisol assay were not available. All subjects with one hour post ACTH cortisol response <18 g/dL or incremental cortisol rise <9 g/dL were diagnosed as having poor cortisol response. Results: The study carried out on two comparative groups showed no difference in basal or Post ACTH cortisol on exposure to high altitude in patients who had developed HAPO from those who did not. The mean increment in serum cortisol or the Delta cortisol was also similar between two groups. The beneficial effect of Dexamethasone in HAPO is not due to relative adrenal insufficiency but due to its potent anti–inflammatory effects, enhanced alveolar fluid clearance and stabilisation of pulmonary endothelial membranes. Conclusion: The altitude–induced rise of many hormones provides evidence that acute exposure to hypoxia tends to stimulate the neuroendocrine system. The serum cortisol levels in our study showed no difference in HAPO patients and the controls. Although drugs are frequently used to prevent or treat high altitude illness, the primary recommendation to decrease its incidence is staged/gradual ascent and progressive acclimatization while cornerstone of its treatment by gradual and passive descent to lower altitude and oxygenation. The steroids only act via its potent anti–inflammatory effects, enhanced alveolar fluid clearance and stabilisation of pulmonary endothelial membranes.