Background: Skeletal muscle has recently been identified as an organ that produces and releases cytokines, named “myokines”. Brain derived neurotropic factor (BDNF), a neurotrophic factor family, is one of myokines and plays a key role in regulating survival, growth and maintenance of neurons. We investigated whether serum BDNF level at discharge could predict the prognosis in patients with heart failure (HF). Methods: We prospectively enrolled 94 patients who were hospitalized for worsening HF and had cardiac rehabilitation. Functional status was evaluated by using cardiopulmonary exercise test (CPX) to measure peak oxygen uptake (PeakVO2) at discharge. We measured serum BDNF level before CPX. Results: Although correlation was not observed between BDNF and PeakVO2 (r = 0.167), slight correlation was observed between BDNF and VE vs VCO2 slope (r = −0.220). Receiver operating characteristic (ROC) curve was used to detect the optimal cut-off point of BDVF (19.22 ng/ml) to estimate event free rate. Kaplan-Meier analysis demonstrated that cardiac death or rehospitalization due to worsening HF was significantly higher in the low BDNF group (P = .02). Multivariate analysis adjusted for Age, peakVO2 and VE vs VCO2 slope found BDNF as an independent factor of adverse events (hazard ratio 0.94, 95% confidence interval 0.90–0.99, P < .01). Conclusions: Serum BDNF level at discharge may be a useful biomarker for the prognosis in patients with HF.