Two trial programmes testing an anti-cytokine medication in chronic heart failure (CHF) have been halted. In the RENAISSANCE and RECOVER trials (the combined analysis being termed RENEWAL), 2048 CHF patients were randomised to placebo or one of 3 doses of etanercept, a fusion protein directed against TNF. Within RENAISSANCE and RECOVER a clinical composite score was used to assess the clinical effects at 24 weeks (primary endpoint: alpha 0.04). Overall, the number of patients who were classified to have during the trial “improved”, remained “unchanged” or “worsened” was similar for patients on placebo or any dose of etanercept (RENAISSANCE: p=0.17, RECOVER: p=0.34). In RENEWAL (combined analysis of medium and high dose etanercept vs. placebo), the primary endpoint (death or CHF hospitalisation, alpha 0.01) was not different between etanercept and placebo (RR 1.10, 95%CI 0.91 to 1.33, p=0.33). In RENEWAL, the secondary endpoint (death for any cause) was not different between etanercept and placebo (RR 1.13, 95%CI 0.86 to 1.50, p=0.39). ATTACH was a phase II, multicentre, randomised, double-blind, placebo-controlled pilot trial that aimed to evaluate the effects of infliximab (an antibody against TNF given in 2 different doses) in 150 CHF patients with stable NYHA class III or IV (in NYHA IV: <10%). In the placebo group (n=49), none of the patients died during 28 weeks of follow-up. At 14 (28) weeks, the endpoint of death or hospitalisation was reached in 2 (5) patients on placebo, in 2 (4) patients in the medium dose (5 mg/kg), and in 8 (13) patients in the high dose (10 mg/kg) of infliximab. During follow-up, compared to placebo the hazard to reach this endpoint was similar in the medium dose group (RR 0.80, 95%CI 0.22–2.99), but increased in the high dose group (RR 2.84, 95%CI 1.01–7.97, p<0.05). Conclusion: At the respective lower doses there was no safety issue with regards to the use of either infliximab or etanercept. High dose anti-TNF therapy may not be useful in CHF patients, but the situation in lower doses and in patients with documented inflammatory/metabolic problems or in cardiac cachexia has not yet been adequately assessed.