To analyze the association of circulating dehydroepiandrosterone sulfate (DHEA-S) levels with cardiovascular outcomes in patients with chronic Chagas cardiomyopathy (CCM) diagnosis. DHEA-S is among the main endogenous steroid hormones. Some studies have suggested a relevant role of this hormone in infections and the setting of CCM. Nevertheless, no study has evaluated the prognostic role of DHEA-S in CCM patients. Prospective cohort study. Patients with CCM and reduced ejection fraction were included. We explored the association of DHEA-S levels with NT-proBNP levels and echocardiographic variables using linear regression models. Next, by using Cox Proportional Hazard models, we examined whether levels of DHEA-S could predict a composite outcome (CO) including all-cause mortality, cardiac transplantation, and implantation of a left ventricular assist device (LVAD). Seventy-four patients were included (59% males, median age: 64 years). After adjustment for confounding factors, high DHEA-S levels were associated with better LVEF, lower left atrium volume, end-systolic volume of the left ventricle and lower NT-proBNP levels. 43% of patients experienced the CO during a median follow-up of 40 months. Increased levels of DHEA-S were associated with a lower risk of developing the CO (HR 0.43; 95%CI 0.21-0.86). Finally, adding DHEA-S to the multivariate model did not improve the prediction of the CO, but substituting NT-proBNP in the model with DHEA-S showed similar performance. In patients with CCM, higher DHEA-S levels were associated with lower mortality, heart transplantation, and LVAD implantation. Further larger studies are required to confirm our results and assess causality. Central illustration. In the present study, lower circulating dehydroepiandrosterone sulfate (DHEA-S) levels were associated with a higher risk of adverse major cardiovascular outcomes (cardiovascular mortality, LVAD implantation, and heart transplantation) in patients with Chronic Chagas Cardiomyopathy (CCM). Several mechanisms may explain the potential protective role of DHEA-S in CCM, either by direct or indirect processes. T. cruzi can impair dehydroepiandrosterone and DHEA-S synthesis in the adrenal glands by direct invasion of the adrenal tissue and/or by promoting the release of proinflammatory cytokines such as TGF-β. Display omitted •Chronic Chagas Cardiomyopathy (CCM) is characterized by a high morbimortality.•In CCM patients, DHEA-S levels were associated with better LVEF and lower NT-proBNP.•Increased DHEA-S levels were associated with a lower risk of mortality.•DHEA-S predictive value was independent of LVEF and NT-proBNP.•DHEA-S may be useful as a biomarker for mortality prediction in CCM patients.