OBJECTIVE The long-term prognostic value of the B-type natriuretic peptide (BNP) level and cardiopulmonary exercise testing in patients with heart failure (HF) who are receiving beta-blocker therapy is not well established. METHODS The study involved 80 outpatients (78% male, age 50 [11] years) with stable HF, severe systolic dysfunction (left ventricular ejection fraction 25 [9]%), and intermediate functional impairment (New York Heart Association functional class 2.4 [0.6]) who were receiving optimum therapy, including beta-blockers. Their BNP levels (pg/mL) were measured and cardiopulmonary exercise testing was carried out to determine maximal oxygen uptake (VO2max) and ventilatory efficiency (VE/VCO2 slope). Patients were followed up for 2.7 (0.8) years. The study endpoints were cardiovascular death, heart transplantation, and HF hospitalization. RESULTS The BNP level and VE/VCO2 slope were greater in patients who died (n=7), at 211 pg/mL (51-266 pg/mL) vs. 46 pg/mL (16-105 pg/mL) (P=.017) and 39 (3) vs. 33.8 (5.5) (P=.018), respectively, or who had an adverse event (n=19), at 139 pg/mL (88-286 pg/mL) vs. 40 pg/mL (13-81 pg/mL) (P< .001) and 38.7 (4.3) vs. 32.9 (5.2) (P< .001), respectively. Only the combined endpoint was associated with a significant difference in VO2max (19.7 [5.4] vs. 16.8 [3.9] mL/kg per min, P=.016). On multivariate analysis, BNP >102 pg/mL (P=.002; hazard ratio [HR]=5.2; 95% confidence interval [CI], 1.8-14.8) and VE/VCO2 slope >35 (P=.012; HR =4.3; 95% CI, 1.4-13.2) were the best predictors of an adverse event. In patients who satisfied neither, one or both criteria, 36-month cumulative adverse event rates were 2%, 25% and 63%, respectively (log rank, P< .001). CONCLUSIONS In ambulatory HF patients with intermediate functional impairment who are receiving optimum beta-blocker therapy, the persistence of a high BNP level (>102 pg/mL) combined with poor ventilatory efficiency (VE/VCO2 slope >35) identify those with a poor long-term prognosis.