Chronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. This study determined whether peak oxygen uptake (VO₂) can be predicted by the degree of neurohormonal and cytokine activations in CHF. Plasma norepinephrine, epinephrine, renin-angiotensin system activity, ANP, BNP, and serum interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α were measured in 84 CHF patients (age, 59 ± 1 years, LVEF, 36 ± 1%) and 34 controls. Maximal cardiopulmonary exercise testing was performed. Peak VO₂ (Controls vs CHF: 27.8 ± 1.3 vs 18.2 ± 0.5 mL/min/kg, P < 0.0001) was lower in CHF. Patients with CHF had increased plasma norepinephrine (211 ± 11 vs 315 ± 24 pg/mL), renin activity (1.2 ± 0.2 vs 6.2 ± 1.1 ng/mL/hr), ANP (22 ± 3 vs 72 ± 7 pg/mL), and BNP levels (18 ± 3 vs 200 ± 25 pg/mL) (all P < 0.01). Serum IL-6 (1.1 ± 0.1 vs 2.4 ± 0.3 pg/mL) and TNF-α (2.7 ± 0.2 vs 4.0 ± 0.3 pg/mL) levels were higher in CHF (both P < 0.001). Univariate analysis revealed that age (P < 0.001), cardiothoracic ratio (P < 0.001), norepinephrine (P < 0.0001), ANP (P < 0.001), BNP (P < 0.01), and log IL-6 (P < 0.05) were significantly related with peak VO₂. Stepwise regression analysis indicated that plasma norepinephrine and ANP emerged as significant determinants of peak VO₂, independent of patient age (overall R = 0.61, P < 0.0001). In summary, patients with CHF exhibited activation of neurohormones and proinflammatory cytokines. Among the elevated hormonal and cytokine markers, plasma norepinephrine and ANP levels were independent predictors of exercise capacity.