Urocortin (UCN), a member of the corticotrophin-releasing factor family, is expressed in heart, brain and gut. UCN has potent cardiostimulatory, cardioprotective, vasodilator and diuretic/natriuretic effects, and cardiac UCN expression is increased in heart failure (HF). In the present study, we investigated plasma levels of UCN in 119 patients with HF and 212 age- and gender-matched controls to clarify its relationship with gender and disease severity. UCN was elevated in HF [normal males, 19.5 (3.9-68.8) pmol/l and HF males, 50.2 (6.9-108.2) pmol/l, P < 0.0005; normal females, 14.2 (3.9-53.5) pmol/l and HF females, 21.8 (3.9-112.5) pmol/l, P < 0.001; values are medians (range)]. The relative increase was greater in males than females ( P < 0.03). UCN fell with increasing age, especially in HF patients ( r(s) = -0.56, P < 0.0005) and with increasing New York Heart Association (NYHA) class ( r(s) = -0.55, P < 0.0005). The fall in UCN levels with increasing NYHA class was reinforced by a significant correlation between UCN and ejection fraction ( r(s) = 0.45, P < 0.0005) in HF patients. Although receiver operating characteristic (ROC) curves for diagnosis of all HF cases yielded an area under the curve (AUC) of 0.76, ROC AUCs for patients with early HF (NYHA class I and II) were better (0.91). ROC AUCs for logistic models incorporating N-terminal probrain natriuretic peptide (N-BNP) and UCN were better than either peptide alone. In conclusion, plasma UCN is elevated in HF, especially in its early stages. Its decline with increasing HF severity may expedite disease progression due to diminished cardioprotective/anti-inflammatory effects. UCN measurement may also complement N-BNP in the diagnosis of early HF.