Background Angiotensin-converting enzyme (ACE) inhibitors are established as first-line therapy in chronic heart failure (CHF). However, conflicting results exist regarding the dose-effect relation of ACE inhibitors. Methods We investigated 45 patients (age 55 ± 10 years) with stable CHF who presented with a maintenance dosage of enalapril of either 5 mg given twice daily (E10; n = 16), 10 mg given twice daily (E20; n = 18), or 20 mg given twice daily (E40; n = 11). This dosage was changed 3 times to treat all patients with lower, higher, and the initial dosages for 4 weeks each. Neurohormones (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and norepinephrine) and enalaprilat trough levels were measured, and ergospirometry was performed. Results Changes in enalapril dose and enalaprilat level were concordant in 82% of patients, indicating good compliance. After augmentation of enalapril to 40 mg daily, patients in the E10 group showed an increase in maximal oxygen consumption and a decrease in neurohormonal stimulation, whereas the opposite changes were observed after reduction of enalapril to 10 mg daily in patients in the E20 and E40 groups (maximal oxygen consumption: Δ1.1 ± 2.0 vs –1.0 ± 1.9 mL · kg^–1 · min^–1, P < .01; ANP: Δ–63 ± 106 vs 19 ± 54 pg/mL, P < .01; BNP: Δ–62 ± 104 vs 18 ± 89 pg/mL, P < .05; norepinephrine: Δ–1.3 ± 2.9 vs 0.6 ± 1.8, P < .05). Within-patient comparison showed that neurohormone levels were higher and exercise capacity lower while patients were receiving 10 mg of enalapril per day than when they were receiving 40 mg per day (ANP: 172 ± 148 vs 139 ± 122 pg/mL, P < .01; BNP: 193 ± 244 vs 152 ± 225 pg/mL, P < .005; norepinephrine: 4.2 ± 2.2 vs 3.5 ± 1.6 nmol/L, P < .05; maximal oxygen consumption 22.0 ± 4.4 vs 21.3 ± 4.3 mL · kg^–1 · min^–1 P < .05). Similar differences were observed when comparing these variables, and patients had lowest and highest enalaprilat trough levels. Conclusions High doses of enalapril resulted in an improvement of exercise capacity and reduction of neurohumoral stimulation, whereas these parameters worsened after reduction of enalapril dose. Thus patients with congestive heart failure may benefit from increasing dosage of ACE inhibitors. (Am Heart J 1999;138:654-62.)