Many patients with hepatitis C chronic infection (HCV+ patients) experience symptoms (fatigue, dyspnea) not proportional to the liver involvement and resemble symptoms of heart failure (HF). To our knowledge, no study evaluated at the same time serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and tumor necrosis factor alpha (TNF-alpha) in HCV+ patients. Circulating NT-proBNP and TNF-alpha were assayed in 60 HCV+ patients, and in 60 sex- and age-matched controls. HCV+ patients showed significantly higher mean NT-proBNP and TNF-alpha levels than controls (P < 0.003). By defining high NT-proBNP level as a value higher than 125 pg/mL (the single cutoff point for outpatients under 75 years of age), 28% of HCV+ and 7% controls had high NT-proBNP (chi-square; P < 0.002). With a cutoff point of 900 pg/mL (that should be used for ruling in HF in patients age 50-75; such as the patients in our study), 3% HCV+ and 0 controls had high NT-proBNP. In conclusion, the study demonstrates high levels of circulating NT-proBNP and TNF-alpha in HCV+ patients. The increase of NT-proBNP may indicate the presence of a subclinical cardiac dysfunction. Further prospective studies quantifying symptoms and correlating these with echocardiographic parameters are needed to confirm this association.