Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) is considered as an effective predictor for patients with heart failure (HF), while a strong body of evidence has found its utility in inflammatory diseases. It is difficult to differentiate HF and HF coexisting with other inflammations by measuring NT-proBNP. The aim of this study was to estimate the differential diagnostic performance of serum NT-proBNP in hospitalized HF patients with pneumonia. A prospective study was launched. Sixty nine HF patients, 51 HF patients complicated with pneumonia, and 38 patients with pneumonia were enrolled. Serum NT-proBNP levels were measured on Roche Elecsys. X-ray and the European Society of Cardiology (ESC) diagnostic principles were adopted to identify patients with pneumonia and HF, respectively. The diagnostic performance of NT-proBNP was assessed by ROC. Serum NT-proBNP [7,039(1,008-24,672) pg/ml] in patients of HF complicated with pneumonia was significantly higher than that in those of patients with single HF [3,147(616-24,062) pg/ml] or single pneumonia [911(98-3,812) pg/ml] (P < 0.0001). No correlation was found between the level of NT-proBNP and hospital stay. The area under ROC curve (AUC) of NT-proBNP for distinguishing patients of HF with pneumonia was 0.8082. At the level of 4,691 pg/ml, the optimal cutoff value, 74.5% sensitivity and 81.8% specificity of NT-proBNP were predicted. Evaluation of serum NT-proBNP is conducive for clinicians to identify patients of HF with pneumonia, but its poor efficacy in monitoring the curative therapy in this entire cohort is not recommended.