We assessed the safety and efficacy of intravenous pentoxifylline [3,7-dimethyl-1-(5-oxohexyl)-xanthine] in patients at risk for developing multiple organ failure after major cardio-thoracic surgery in a single-center, randomized, placebo-controlled study. Of 816 consecutive patients who underwent major cardio-thoracic surgery, 40 who had Acute Physiology and Chronic Health Evaluation II score values ≥19 at the first postoperative day after the surgery were included. Patients were randomized to receive either placebo (control; n = 25) or intravenous pentoxifylline treatment (pentoxifylline; n = 15) at a dosage of 1.5 mg/kg/h as an adjunct to standard supportive therapy. Main outcome measurements were duration of required ventilator support, intensive care unit stay, and incidence of renal failure. Thirty-seven patients were eligible for evaluation. No significant adverse events related to pentoxifylline treatment were observed. The duration of mechanical ventilation was significantly greater for control patients (8.3 ± 3.1 days) compared with pentoxifylline-treated patients (3.1 ± .9 days; p < .05). Patients treated with pentoxifylline experienced fewer days on hemofiltration (1.2 ± .8 vs. 6.8 ± 3.3; p < .05) and a shorter intensive care unit stay (5.2 ± 1.1 vs 11.4 ± 3.1 days). There were no intergroup differences in mortality. Mortality was 33% in the pentoxifylline group and 36% among control group patients. In conclusion, supplemental pentoxifylline treatment may decrease the incidence of multiple organ failure in patients at risk of systemic inflammatory response syndrome after cardiac surgery. Additional studies are required to determine the validity of the observed effects.