Background: In chronic heart failure (CHF), cardiac dysfunction is considered the major determinant of neurohumoral activation but the role of renal impairment has not been defined. We investigated the relationship between both cardiac and renal dysfunction and neurohumoral activation, and their possible influence on prognosis. Methods: Hemodynamics, renal function, plasma neurohormones, and long-term follow-up were evaluated in 148 CHF patients, grouped according to systolic volume index (SVI) and serum creatinine (CRE) values: SVI > 28 mL/m(2) and CRE < 1.5 mg/dL(group I, n = 55), SVI < 28 mL/m2 and CRE < 1.5 mg/dL (group II, n = 37), SVI > 28 mL/m(2) and CRE > 1.5 mg/dL (group III, n = 25), SVI < 28 mL/m(2) and CRE > 1.5 mg/dL (group IV, n = 31). Results: Neurohormones progressively increased from Group I through IV and correlated with both cardiac and renal function. The hemodynamic pattern was similar in patients with normal or abnormal renal function, whereas neurohormones were only moderately increased in the former group and markedly increased in the latter group. Longterm survival progressively decreased from Group through IV and was significantly poorer in patients with renal dysfunction. Conclusions: Our study confirms that, in CHF, neurohumoral activation is strictly related to long-term survival and that many factors contribute to its development and progression; among these, cardiac and renal dysfunction seem to play a major role.