Pancreatitis-associated protein (PAP) is a novel cytokine with putative anti-inflammatory effects. PAP gene expression has been found to be increased in the myocardium of rats with decompensated pressure-overload hypertrophy. A prospective pilot study was performed to test the hypotheses that PAP is elevated in ambulatory patients with heart failure (HF) and that concentrations correlate with the severity of disease. Blood samples were obtained from patients with HF (n = 70) and normal controls (n = 17). Patients with New York Heart Association class III and IV symptoms had a greater mean PAP than patients with class I and II symptoms (35.5 ± 4.0 vs 10.3 ± 1.0 μg/L, p <0.001) and normal controls (35.5 ± 4.0 vs 6.2 ± 0.5 μg/L, p <0.001). Receiver-operating characteristic curves revealed that PAP had similar sensitivity and specificity for HF admission at 6 months as B-type natriuretic peptide and equivalent predictive value for 12-month and 24-month all-cause mortality. On the basis of the receiver-operating characteristic curve analysis, patients were then grouped into those with a serum PAP <24 or ≥24 μg/L. Patients with PAP ≥24 μg/L had significantly worse renal function, greater B-type natriuretic peptide and C-reactive protein levels, higher pulmonary artery systolic pressure, and greater 6- and 24-month all-cause mortality (p <0.05). In conclusion, PAP levels correlate with disease severity in patients with HF and are a marker of cardiorenal syndrome, neurohormonal activation, and elevated filling pressures. PAP is a sensitive and specific marker for increased 6-month HF morbidity and 12- and 24-month all-cause mortality. These results justify the prospective evaluation of PAP as a novel prognostic marker for disease severity in patients with HF.