Abstract Aims Women continue to have a worse prognosis following ST-elevation myocardial infarction (STEMI) compared to men, despite advancements in treatment. This study investigates whether neurohormonal biomarker differences contribute to sex-related disparities in mortality. Methods and results A total of 1892 consecutive STEMI patients from two tertiary heart centres were included. Admission neurohormonal activation defined as pro-atrial natriuretic peptide (proANP) and mid-regional pro-adrenomedullin (MR-proADM) was measured in blood drawn prior to acute coronary angiography (CAG). The primary endpoint was 1-year mortality stratified according to sex and biomarker level. Of 1782 (94%) with biomarkers available, 476 (27%) of patients were women. They were older (68 vs. 62 years), had longer symptom-to-angiography delay (211 vs. 181 min), and displayed a higher one-year mortality rate (12% vs. 7.4%, P < 0.001) compared to men. The neurohormonal response was higher in women compared to men [median (interquartile range) proANP 1050 (671–1591) vs. 772 (492–1294) pmol/L, P < 0.001); MR-proADM 0.80 (0.63–1.03) vs. 0.70 (0.58–0.89) nmol/L, P < 0.001]. In women, a level at or above the median was independently associated with a significantly higher mortality risk when adjusting for age, left ventricular ejection fraction, diabetes, heart failure, symptom onset to CAG, left-sided culprit lesion, obesity, renal dysfunction, primary percutaneous intervention, admission systolic blood pressure, and multivessel disease (HR proANP 6.05, 95% CI 1.81–20.3, P = 0.004; HR MR-proADM 3.49, 95% CI 1.42–8.62, P = 0.007). In men, there was an independent prognostic association for proANP but not for MR-proADM (HR proANP 2.38, 95% CI 1.18–4.81, P = 0.015; HR MR-proADM 1.74, 95% CI 0.89–3.40, P = 0.11). Conclusion Increased neurohormonal activation (MR-proADM and proANP) is associated with higher mortality in women compared to men. Neurohormonal activation may contribute to the observed sex-related differences in mortality.