Objective To determine the predictive value of pro-C-type natriuretic peptide (pro-CNP) measurement in plasma sampled on admission from patients presenting with ST-elevation myocardial infarction (STEMI). Design Prospective cohort study. Setting Two University Hospitals in Denmark. Participants 1760 consecutive patients (470 females and 1290 males) with confirmed STEMI. Main outcomes and measures The main outcome was all-cause mortality at 1 year after presentation and the primary measure was pro-CNP concentration in plasma at admission in all patients and longitudinal measurements in a consecutive subgroup of 287 patients. A reference population (n=688) defined cut-off values of increased pro-CNP concentrations. Results In all patients, an increased pro-CNP concentration was associated with a higher all-cause mortality after 1 year (HR 1.6, 95% CI 1.1 to 2.4, P-logrank=0.009) including an interaction of sex (p=0.03). In separate sex-stratified analyses, female patients showed increased all-cause mortality (HR1 year 2.6, 95% CI 1.5 to 4.6), P-logrank = the median value to be independently associated with increased risk of mortality in female patients within 1 year (HR per 1 pmol/L increase: 1.04, 95% CI 1.01 to 1.06, p=0.007). Moreover, we found indications of sex differences in pro-CNP concentrations over time (higher pro-CNP in males (4.4, 95% CI -0.28 to 9.1 pmol/L, p=0.07) and interaction of sex and time (p=0.13)), and that hypertension was independently associated with higher pro-CNP (4.5, 95% CI 0.6 to 8.4 pmol/L, p=0.03). Conclusions In female but not male patients presenting with STEMI, high concentrations of pro-CNP (>= median) at admission independently indicate a higher risk of all-cause mortality. The findings are remarkably specific for female patients, suggesting a different vascular phenotype beyond traditional measures of coronary artery flow compared with male patients.