Cytokines are soluble peptides that mediate cell-to-cell interactions via specific cell surface receptors. There is a growing body of evidence that cytokines may play an important role in the pathogenesis of heart failure, and the intriguing possibility has been postulated that anticytokine therapy may favorably alter the clinical outcome of heart failure. As cytokines are essentially pleiotropic and redundant in nature, elimination of a single cytokine from the biologic system often fails to have major consequences. Therefore, the prospect has been raised for developing immunomodulating therapy for heart failure, enabling the simultaneous modification of the actions of multiple cytokines. The recently observed clinical benefit of vesnarinone on mortality and morbidity in patients with heart failure has been attributed to this immunomodulation. In the murine model of myocarditis and heart failure, vesnarinone enhanced the cumulative survival rate without affecting virus replication on virus-induced cytopathic effects. Vesnarinone inhibited excessive cytotoxicity of natural killer cells presumably by suppressing activation mediated by K channel inhibition. Vesnarinone also inhibited the production of cytokines. Cytokine inhibitory effects were different from those of other phosphodiesterase inhibitors or direct elevation of intracellular cyclic adenosine monophosphate, suggesting that the effects did not appear to be derived solely from a cyclic adenosine monophosphate-elevating action. Such cytokine regulation also appeared to be different in normal patients and in patients with heart failure. In conclusion, vesnarinone exerts an immunomodulating effect by suppressing natural killer cell activity and inhibiting cytokine production. These findings may hold open the hope that immunomodulation could be a new therapeutic modality. However, further studies on the long-term safety and efficacy of vesnarinone are warranted to establish the eventual status of this agent in the treatment of heart failure.