Patients with severe heart failure have plasma cytokine concentrations that are more than twofold greater than those in patients with moderate heart failure. Although pentoxifylline, an immunomodulatory agent that inhibits tumour necrosis factor-alpha (TNF-alpha) production, improves pump function in mild-to-moderate heart failure, its effects on advanced heart failure have not been determined. In a prospective, randomized, double-blind, placebo-controlled study we compared the effects of 1-month therapy with pentoxifylline (400 mg 3 times daily) (n = 9) and placebo (n = 9) on left ventricular systolic function and dimensions as well as on plasma TNF-alpha (picograms per milliliter), interleukin-10 (IL-10), and the apoptosis-signaling receptor Fas/Apo-1 in patients with idiopathic dilated cardiomyopathy and advanced heart failure. All patients had New York Heart Association functional class IV heart failure, required intravenous inotropic agents for >72 hours at the beginning of the study, and received diuretics, digoxin, and an angiotensin-converting enzyme inhibitor for the duration of the study. Marked increases in TNF-alpha and Fas/Apo-1 concentrations were noted in the 18 patients compared with patients with functional class II to III heart failure and controls (p <0.001). Baseline characteristics were the same between the pentoxifylline and placebo groups. Pentoxifylline administration resulted in reduced TNF-alpha and Fas/Apo-1 concentrations, and an increase in ejection fraction at 1 month (p <0.05 compared with baseline and with placebo), effects that were not observed in the placebo-treated group. These data suggest that pentoxifylline may be a useful adjunct to conventional therapy in patients with severe heart failure.