Abstract Background Elderly patients with heart failure (HF) have a worse prognosis than younger patients. We wished to study whether elders benefit from natriuretic peptide-guided HF care in this single-center study. Methods and Results A total of 151 patients with HF resulting from left ventricular systolic dysfunction (LVSD) were treated with HF treatment by standard-of-care (SOC) management or guided by N-terminal pro-B type natriuretic peptide (NT-proBNP) values (with a goal to lower NT-proBNP ≤1000 pg/mL) over 10 months. The primary end point for this post-hoc analysis was total cardiovascular events in 2 age categories (<75 and ≥75 years). In those ≥75 years of age (n = 38), NT-proBNP values increased in the SOC arm (2570 to 3523 pg/mL, P  = .01), but decreased in the NT-proBNP–guided arm (2664 to 1418 pg/mL, P  = .001). Elderly patients treated with SOC management had the highest rate of cardiovascular events, whereas the elderly with NT-proBNP management had the lowest rate of cardiovascular events (1.76 events per patient versus 0.71 events per patient, P  = .03); the adjusted logistic odds for cardiovascular events related to NT-proBNP–guided care for elders was 0.24 ( P  = .008), whereas in those <75 years (n = 113), the adjusted logistic odds for events following NT-proBNP–guided care was 0.61 ( P  = .10). Conclusions Natriuretic peptide–guided HF care was well tolerated and resulted in substantial improvement in cardiovascular event rates in elders (Clinical Trials.Gov #00351390).