The safety and benefit of outpatient inotrope infusions in intractable heart failure remains controversial. Accordingly a prospective double blind, crossover randomization scheme was utilized in stable patients with heart failure but intractable symptoms. A total of 29 patients (mean age 66 +/- 13 years, with a mean left ventricular systolic function of 18 +/- 9%, New York Heart Association class 3.6 +/- 0.5) met all the inclusion and none of the exclusion criteria to receive intravenous milrinone, dobutamine, or matching placebo. Safety evaluations including routine laboratory studies, physical examinations, electrocardiographic monitoring, vital signs, assessment of quality of life scores using the Minnesota Living with Heart Failure questionnaire, six-minute walk tests, and echocardiographic assessments were performed. All 29 patients completed the weaning protocol without adverse events (mean of 27.3 +/- 11.8 treatments per patient). Patients initially assigned to milrinone received fewer treatment sessions (19 +/- 8 versus 31 +/- 12 (dobutamine) and 33 +/- 10 (placebo); p<0.02. Furthermore, only 10% of the patients treated with milrinone required crossover randomization compared to 27% patients assigned to dobutamine and 75% patients assigned to placebo. A statistically significant reduction in quality of life scores (60 +/- 20 versus 35 +/- 18; p < 0.00001) with an increase in 6-minute walk test assessments (959 +/- 431 versus 1269 +/- 469; p < 0.01) was noted. Most importantly, in patients assigned to inotropes a 23% increase in 6-minute walk test scores was noted at the end of the study when compared to baseline scores. In contrast, a reduction of -1% (p < 0.001) was noted in patients assigned to placebo. Finally, a trend that although did not reached statistical significance was noted in patients assigned to milrinone in terms of improvement in left ventricular systolic function, reduction in the severity of mitral regurgitation and estimated right ventricular systolic pressure. These results demonstrate that outpatient infusion of inotropes appear to be safe and effective in improving heart failure symptoms, reducing need for hospitalizations and emergency room visits. Furthermore, infusion of inotropes resulted in a significant improvement on 6-minute walk test scores than placebo. It also appears that milrinone confers all these benefits sooner than dobutamine.