Objective We investigated the relative effects of fatigue, depressive symptoms, and hopelessness on prognosis at 2-year follow-up in percutaneous coronary intervention (PCI) patients. Methods Consecutively admitted PCI patients (n=534) treated with paclitaxel-eluting stent as the default strategy completed the Maastricht Questionnaire (MQ) at baseline. Apart from an overall vital exhaustion score, the MQ also assesses fatigue (seven items; Cronbach's α=.87) and depressive symptoms (seven items; Cronbach's α=.83), with hopelessness (one item) comprised in the depressive symptom items. Patients were followed up for adverse clinical events (mortality and nonfatal myocardial infarction) at 2 years. Results At 2-year follow-up, there were 31 clinical events. In univariable analyses, overall vital exhaustion and depressive symptoms, but not fatigue, were associated with adverse prognosis; in multivariable analysis, depressive symptoms [hazard ratio (HR)=2.69; 95% confidence interval (95% CI)=1.31–5.55] remained the only predictor of clinical outcome. Among the depressive symptoms, hopelessness (HR=3.44; 95% CI=1.65–7.19) was the most cardiotoxic symptom. The incidence of clinical events was higher in the high-hopelessness patients (11% vs. 3%; P=.001) than in the low-hopelessness patients. Hopelessness (HR=3.36; 95% CI=1.58–7.14; P=.002) remained an independent predictor of clinical outcome at 2 years in adjusted analysis. Conclusion Symptoms of depression, but not fatigue, predicted adverse clinical events. Hopelessness was the most cardiotoxic symptom, associated with a more than three-fold risk of clinical events 2 years post-PCI. Screening for hopelessness may lead to the identification of high-risk patients.