We previously reported that intracoronary implantation of bone marrow mononuclear cells (BMMC) into ischemic hearts improved cardiac function after myocardial infarction. However, the mechanisms have not been elucidated. The present study investigates whether apelin, a newly described inotropic peptide with important cardiovascular regulatory properties, contributes to the functional improvement in patients with severe heart failure after cell transplantation. Forty consecutive patients with severe heart failure secondary to myocardial infarction were assigned to the BMMC therapy group or the standard medication group according to each patient's decision on a signed consent document. In 20 patients intracoronary cell infusion was performed, and another 20 patients were matched to receive standard medication as therapeutic controls. An additional 20 healthy subjects were designated as normal controls. Clinical manifestations, echocardiograms, and biochemical assays were recorded. Plasma apelin and brain natriuretic protein (BNP) levels were determined by enzyme immunoassay. Baseline levels of plasma apelin were significantly lower in all heart failure patients compared to normal subjects. In patients who underwent cell transplantation, apelin increased significantly from 3 to 21 days after operation, followed by significant improvement in cardiac function. In parallel, BNP varied inversely with the increase of apelin. In patients receiving standard medical treatment, apelin remained at a lower level. Our findings indicated that increased apelin levels following cell therapy may act as a paracrine mediator produced from BMMCs and play an important role in the treatment of heart failure through autocrine and paracrine mechanisms.