Background: The N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) is a powerful predictor of adverse outcomes in patients with coronary artery disease (CAD). However, little is known regarding the prognostic significance of longitudinal changes in NT-proBNP levels. Methods: We evaluated the ability of 5-year changes in NT-proBNP levels to predict subsequent heart failure (HF) hospitalization or cardiovascular (CV) death in 635 participants with stable CAD enrolled in the Heart and Soul Study. Results: The median (IQR) 5-year change in NT-proBNP was 50 pg/mL (-5 to +222). During an average of 4.0 ± 1.4 years follow-up (i.e., 9 years from the baseline measurement), there were 67 events. Participants with 5-year changes in the highest quartile (≥ 223 pg/mL increase in NT-proBNP) had an almost 4-fold greater risk of subsequent HF or CV death than those in the lowest quartile of ≤-5 pg/mL (HR 3.8; 95% CI 2.0-7.3; p < 0.001). This association remained strong after adjustment for demographic variables, comorbidities, left ventricular mass index, systolic and diastolic function, and baseline and follow-up NT-proBNP levels (HR 3.9; 95% CI 1.1-13.4; p = 0.01). Conclusion: Changes in NT-proBNP levels at 5 years predict subsequent HF or CV death in patients with stable CAD, independent of other prognostic markers, including baseline and follow-up NT-proBNP levels. A stable NT-proBNP level predicts a low risk of subsequent events.