Data supporting the use of oral isosorbide dinitrate and/or hydralazine (I/H) as add-on therapy to standard neurohormonal antagonists in advanced decompensated heart failure (ADHF) are limited, especially in the non-African-American population. Our objective was to determine if addition of I/H to standard neurohormonal blockade in patients discharged from the hospital with ADHF is associated with improved hemodynamic profiles and improved clinical outcomes. We reviewed consecutive patients with ADHF admitted from 2003 to 2006 with a cardiac index ≤2.2 L/min/m2 admitted for intensive medical therapy. Patients discharged with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (control group) were compared with those receiving angiotensin-converting enzyme inhibitors/angiotensin receptor blockers plus I/H (I/H group). The control (n = 97) and I/H (n = 142) groups had similar demographic characteristics, baseline blood pressure, and renal function. Patients in the I/H group had a significantly higher estimated systemic vascular resistance (1,660 vs 1,452 dynes/cm5, p <0.001) and a lower cardiac index (1.7 vs 1.9 L/min/m2, p <0.001) on admission. The I/H group achieved a similar decrease in intracardiac filling pressures and discharge blood pressures as controls, but had greater improvement in cardiac index and systemic vascular resistance. Use of I/H was associated with a lower rate of all-cause mortality (34% vs 41%, odds ratio 0.65, 95% confidence interval 0.43 to 0.99, p = 0.04) and all-cause mortality/heart failure rehospitalization (70% vs 85%, odds ratio 0.72, 95% confidence interval 0.54 to 0.97, p = 0.03), irrespective of race. In conclusion, the addition of I/H to neurohormonal blockade is associated with a more favorable hemodynamic profile and long-term clinical outcomes in patients discharged with low-output ADHF regardless of race.