INTRODUCTION AND AIMS: Selecting patients for heart transplantation is challenging. We aimed to identify the most important risk predictors in heart failure and an approach to optimize the selection of candidates for heart transplantation. METHODS: Ambulatory patients followed in our center with symptomatic heart failure and left ventricular ejection fraction ≤40% prospectively underwent a comprehensive baseline assessment including clinical, laboratory, electrocardiographic, echocardiographic, and cardiopulmonary exercise testing parameters. All patients were followed for 60 months. The combined endpoint was cardiac death, urgent heart transplantation or need for mechanical circulatory support, up to 36 months. RESULTS: In the 263 enrolled patients (75% male, age 54±12 years), 54 events occurred. The independent predictors of adverse outcome were ventilatory efficiency (VE/VCO2) slope (HR 1.14, 95% CI 1.11-1.18), creatinine level (HR 2.23, 95% CI 1.14-4.36), and left ventricular ejection fraction (HR 0.96, 95% CI 0.93-0.99). VE/VCO2 slope was the most accurate risk predictor at any follow-up time analyzed (up to 60 months). The threshold of 39.0 yielded high specificity (97%), discriminated a worse or better prognosis than that reported for post-heart transplantation, and outperformed peak oxygen consumption thresholds of 10.0 or 12.0 ml/kg/min. For low-risk patients (VE/VCO2 slope