Acute coronary syndrome is a frequent cause of morbidity and mortality, and a known stress response trigger. We aim to investigate the association between cortisol, as a primary stress hormone, and prognosis/mortality in this scenario. Single-center, prospective, observational, and analytical study in patients admitted for acute coronary syndrome. Clinical characteristics and prognosis markers were registered, along with serum cortisol levels on admission and in-hospital mortality. Cortisol levels were higher in patients with a depressed ST segment (18.22 ± 13.38 μg/dL), compared to those with an isoelectric ST segment (12.66 ± 10.47 μg/dL), and highest in patients with an elevated ST segment (22.61 ± 14.45 μg/dL), with P< 0.001. Also, cortisol was significantly increased in patients with elevated troponin I values (18.90 ± 14.19 μg/dL vs 11.87 ± 8.21 μg/dL, P< 0.001). Patients with Killip-Kimball class I or II had a lower mean serum cortisol (14.66 ± 10.82 μg/dL) than those with class III or IV (41.34 ± 15.57 μg/dL), P< 0.001. Finally, we found that patients who died during hospitalization had higher cortisol on admission: 36.39 ± 17.85 μg/dL vs 15.26 ± 11.59 μg/dL, P= 0.003. Cortisol was directly related to the electrocardiographic presentation of ACS and with the maximum troponin I value. This indicates that serum cortisol levels parallel the extension of ischemia and myocardial injury, and in this way affect the clinical prognosis, evidenced by the Killip-Kimball class and the increase in mortality.