BACKGROUND: Regular exercise is recommended to improve outcomes in patients with heart failure. Exercise is known to decrease inflammation and thought to decrease myocardial stress; however, studies of exercise in heart failure have had mixed results on levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hsCRP). A multimarker analysis may help to identify distinct subgroups of patients who respond to exercise. Our primary study objective was to identify common and distinct patterns of change in hsCRP and NT-proBNP and to quantify the influence of exercise therapy on the observed patterns of change. METHODS AND RESULTS: NT-proBNP and hsCRP were assessed in a random sample of 320 participants from the biomarker substudy of HF-ACTION, a randomized clinical trial of exercise training versus usual care in patients with stable and chronic heart failure. Growth mixture modeling was used to identify unique biomarker patterns over 12 months. Three statistically independent and clinically meaningful biomarker patterns of NT-proBNP and hsCRP were identified. Two patterns were combined and compared with the "low/stable" pattern, which was characterized by the lowest levels of NT-proBNP and hsCRP over time. Participants who were taking a loop diuretic and had hypertension or ischemic etiology were ∼2 times as likely to be in the "elevated/worsening" biomarker pattern. Participants randomized to the exercise intervention were less likely to be in the elevated/worsening pattern of NT-proBNP and hsCRP (relative risk ratio 0.56, 95% confidence interval 0.32-0.98; P = .04). CONCLUSIONS: Exercise therapy was protective for reducing the frequency of membership in the elevated/worsening biomarker pattern, indicating that exercise may be helpful in delaying the progression of heart failure.