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Patients with heart failure (HF) commonly have unintentional weight loss, depressive symptoms, and elevated levels of high-sensitivity C-reactive protein (hsCRP). Each of these variables has been independently associated with shorter cardiac event–free survival. However, little data exist on the relationships of unintentional weight loss, hsCRP level, and depressive symptoms to cardiac event–free survival.The aims of this study were to determine (1) whether depressive symptoms and elevated hsCRP level predicted unintentional weight loss and (2) whether unintentional weight loss predicted shorter cardiac event–free survival.This was a prospective study of 243 consecutive HF patients (61% men, 61 ± 14 years old) enrolled during an index hospitalization for HF exacerbation. Patients provided blood samples to measure hsCRP level and completed the Beck Depression Inventory to assess depressive symptoms at discharge. Body weight was measured at discharge and 6 months later. Unintentional weight loss was defined as weight loss of greater than 6% of body weight since discharge. Cardiac event–free survival was followed for 1 year after the second measurement of body weight through monthly telephone interviews. Hierarchical logistic regression was used to determine whether depressive symptoms and elevated hsCRP level predicted unintentional weight loss. Cox hazard regression was used to determine whether unintentional weight loss predicted cardiac event–free survival.Thirty-five patients (14.4%) experienced unintentional weight loss at 6 months after discharge. Hierarchical Cox hazard regression revealed that patients with unintentional weight loss had a 3.2 times higher risk for cardiac events, adjusting for other clinical factors (P < .001). In hierarchical logistic regression, elevated hsCRP level (odds ratio, 1.49; 95% confidence interval, 1.15–1.92) and depressive symptoms (odds ratio, 1.07, 95% confidence interval, 1.02–1.12) independently predicted unintentional weight loss.Unintentional weight loss was an independent predictor of poor outcomes. Heart failure patients with depressive symptoms and elevated hsCRP levels are at a higher risk for unintentional weight loss.