Elevated plasma natriuretic peptides in heart failure (HF) usually indicate a poor outcome and low levels a compensated state. In advanced chronic HF, however, low levels may reflect an impaired neurohormonal response. To assess this hypothesis, this study analyzed whether N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and B-type natriuretic peptide (BNP) levels were related to mortality in 40 patients treated for decompensated chronic HF. Cardiovascular mortality during follow-up (10 +/- 1 months) was 40%. BNP levels were lower in patients who died (487 +/- 60 vs 836 +/- 99 pg/ml, p <0.02), as were NT-pro-BNP levels (9,507 +/- 1,178 vs 17,611 +/- 4,338 pg/ml, p <0.05). These data support the hypothesis that patients with end-stage HF and poor short-term survival have lower natriuretic peptide levels than those who survive. These findings suggest that the natriuretic peptide system can no longer contribute adequately to neurohormonal compensation and that paradoxically low peptide levels are an adverse prognostic marker in advanced HF.