Background Patients with stable atherothrombotic disease vary in their risk of developing heart failure (HF). Circulating cardiovascular biomarkers may improve HF risk assessment and identify patients who may benefit from emerging HF preventive therapies. Methods and Results We measured high‐sensitivity cardiac troponin I and BNP (B‐type natriuretic peptide) in 15 833 patients with prior myocardial infarction, ischemic stroke, or peripheral artery disease from the TRA 2°P‐TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events‐Thrombolysis in Myocardial Infarction 50) trial, excluding patients with recent myocardial infarction (<30 days). Biomarkers were categorized using a priori cut points. Hospitalization for HF (HHF) end points were adjudicated with blinded structured review of serious adverse events. Associations between biomarkers and HHF outcomes were adjusted for sex and independent clinical risk predictors of HHF in our cohort (age ≥75, prior HF, type 2 diabetes mellitus, polyvascular disease, body mass index, anemia, chronic kidney disease, hypertension). Baseline high‐sensitivity cardiac troponin I and BNP each identified a significant graded risk of HHF independent of clinical risk predictors, including in the subgroups of patients with and without type 2 diabetes mellitus and with and without prior HF. Patients with both high‐sensitivity cardiac troponin I ≥5 ng/L and BNP ≥100 pg/mL had the highest HHF event rates. When added to a multivariable Cox regression model with clinical risk predictors (C‐index 0.88; 95% CI, 0.85–0.90), BNP (C ‐index 0.92; 95% CI, 0.90–0.93), and high‐sensitivity cardiac troponin I (C‐index 0.90; 95% CI, 0.88–0.92) each significantly improved the prognostic performance of the model (both P _LRT <0.001). Conclusions Biomarkers of myocardial injury and hemodynamic stress are independent predictors of HHF risk in patients with stable atherothrombotic disease, with and without prior HF and/or type 2 diabetes mellitus. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00526474.