Carbohydrate antigen 125 (CA125) is a congestion and inflammation biomarker and has been proved to be related to a worse prognosis in heart diseases. However, the precise relationship between elevated CA125 in patients with ST-segment elevation myocardial infarction (STEMI) has not yet been sufficiently studied. We set out to determine the association of CA125 with all-cause mortality at 6 months in STEMI. CA125, N-terminal pro brain natriuretic peptide (NTproBNP) and high sensitive C-reactive protein (hs-CRP) were measured in 245 patients admitted consecutively with STEMI undergoing coronary angioplasty. The mean age in our sample was 63.7 years, 64.9% were males, 28.3% had diabetes and 17.7% presented with acute heart failure (Killip ≥ 2). The median serum level of CA125 was 8.1 U/ml. At 6 months, the rate of all-cause mortality was 18% (44 patients). Receiver operating characteristic curve analysis demonstrated that CA125 presented similar performance to predict mortality as NTproBNP and hs-CRP. Patients with CA125 ≥ 11.48 had a higher rate of mortality (Hazard Ratio = 2.07, 95% confidence interval = 1.13-3.77, p = 0.017) than patients with CA125 < 11.48. This study suggests that elevated CA125 levels might be used to identify patients with STEMI with a higher risk of death at 6 months. CA125 seems to be a similar predictor of mortality compared to NTproBNP and hs-CRP.