Lymphocytopenia is associated with an adverse prognosis in heart failure (HF). The present study investigated whether lymphocytopenia results from activated lymphocyte autophagy/apoptosis, which reflects haemodynamic inefficiency and functional aerobic impairment in patients with HF. One hundred and twenty-seven patients with HF were divided into three groups: HF with non- (lymphocytes ≥2000 cells/μl; n=45), mild (lymphocytes between ≥1500 cells/μl and <2000 cells/μl; n=39) and severe (lymphocytes <1500 cells/μl; n=43) lymphocytopenia. Lymphocyte autophagy/apoptosis, ventilatory/haemodynamic efficiencies and generic/disease-specific quality of life were analysed in these patients with HF and 35 normal counterparts. The results demonstrated that patients with HF with severe lymphocytopenia had (i) increased G-protein-coupled receptor kinase-2 (GRK-2) levels, (ii) lower mammalian target of rapamycin (mTOR) levels with higher lysosome-associated membrane protein-2 (LAMP-2) expression and Acridine Orange (AO) staining, (iii) lower mitochondrial transmembrane potential with higher caspase-3 activation and phosphatidylserine (PS) exposure, and (iv) greater extents of adrenaline (epinephrine)-induced apoptosis in lymphocytes, and higher plasma noradrenaline (norepinephrine)/adrenaline, myeloperoxidase and interleukin-6 concentrations than patients with HF without lymphocytopenia and normal counterparts did. Moreover, lymphocyte caspase-3 activation was an effect modifier, which modulated the correlation status between lymphocyte count and GRK-2 level. Lymphocyte count was positively correlated with peak cardiac output and peak oxygen consumption (VO2peak) in patients with HF. In addition, HF with lymphocytopenia was accompanied by lower Short Form-36 physical/mental component scores and increased Minnesota Living with Heart Failure Questionnaire scores. Therefore, we conclude that increased sympathetic activation and oxidative stress/pro-inflammatory status cause lymphocytopenia by activating programmed lymphocyte death in patients with HF. Moreover, a low lymphocyte count correlates with reduced haemodynamics and aerobic capacity, which reflects poor generic/disease-specific quality of life in patients with HF.