Context Little randomized evidence is available to guide the in-hospital management of patients with an acute exacerbation of chronic heart failure. Although intravenous inotropic therapy usually produces beneficial hemodynamic effects and is labeled for use in the care of such patients, the effect of such therapy on intermediate-term clinical outcomes is uncertain. Objective: To prospectively test whether a strategy that includes short-term use of milrinone in addition to standard therapy can improve clinical outcomes of patients hospitalized with an exacerbation of chronic heart failure. Design: Prospective, randomized, double-blind, placebo-controlled trial conducted from July 1997 through November 1999. Setting: Seventy-eight community and tertiary care hospitals in the United States. Participants: A total of 951 patients admitted with an exacerbation of systolic heart failure not requiring intravenous inotropic support (mean age, 65 years; 92 % with baseline New York Heart Association class III or IV; mean left ventricular ejection fraction, 23%). Intervention: Patients were randomly assigned to receive a 48-hour infusion of either milrinone, 0.5 μg/kg per minute initially (n=477), or saline placebo (n=472). Main Outcome Measure: Cumulative days of hospitalization for cardiovascular cause within 60 days following randomization. Results: The median number of days hospitalized for cardiovascular causes within 60 days after randomization did not differ significantly between patients given milrinone (6 days) compared with placebo (7 days; P=.71). Sustained hypotension requiring intervention (10.7% vs 3.2%; P<.001) and new atrial arrhythmias (4.6% vs 1.5%; P=.004) occurred more frequently in patients who received milrinone. The milrinone and placebo groups did not differ significantly in in-hospital mortality (3.8% vs 2.3%; P=.19), 60-day mortality (10.3% vs 8.9%; P=.41), or the composite incidence of death or readmission (35.0% vs 35.3%; P=.92). Conclusion: These results do not support the routine use of intravenous milrinone as an adjunct to standard therapy in the treatment of patients hospitalized for an exacerbation of chronic heart failure.