Background Most patients with chronic heart failure (CHF) receive the same dose of angiotensin-converting enzyme (ACE) inhibitors because there is currently no measure of treatment efficacy. We sought to determine whether titration of vasodilator therapy according to plasma brain natriuretic peptide (BNP) concentration may be of value in the individual optimization of vasodilator therapy in CHF. Methods and Results Twenty patients with mild to moderate CHF receiving stable conventional therapy including an ACE inhibitor were randomly assigned to titration of ACE inhibitor dosage according to serial measurement of plasma BNP concentration (BNP group) or optimal empirical ACE inhibitor therapy (clinical group) for 8 weeks. Only the BNP-driven approach was associated with significant reductions in plasma BNP concentration throughout the duration of the study and a significantly greater suppression when compared with empiric therapy after 4 weeks [–42.1% (–58.2, –19.7) vs –12.0% (–31.8, 13.8), P = .03]. Both treatment strategies were well tolerated and associated with favorable neurohormonal and hemodynamic effects; however, in comparison between groups, mean heart rate fell (P = .02) and plasma renin activity rose (P = .03) in the BNP group when compared with the clinical group. Conclusions Plasma BNP concentration may be chronically reduced by tailored vasodilator therapy in CHF. Furthermore, titration of vasodilator therapy according to plasma BNP was associated with more profound inhibition of the renin-angiotensin-aldosterone system and significant fall in heart rate when compared with empiric therapy. (Am Heart J 1999;138:1126-32.)