This was a multicenter, randomized, double-blind, placebo-controlled pilot study, evaluating the safety and efficacy of a standard care treatment regimen with the addition of either nesiritide or placebo (SCP) in 237 Emergency Department (ED)/Observation Unit (OU) patients with decompensated heart failure (HF). Efficacy measures included initial admission, length of hospital stay (LOS), and inpatient rehospitalization through 30 days. Compared to the standard care group, patients who also received nesiritide had 11% fewer inpatient hospital admissions at the index ED visit (55% SCP, 49% nesiritide, p = 0.436), and 57% fewer inpatient hospitalizations within 30 days after discharge from the index hospitalization (23% SCP, 10% nesiritide, p = 0.058). The duration of rehospitalization was shorter for nesiritide patients (median LOS 2.5 vs. 6.5 days, p = 0.032). The incidence of symptomatic hypotension was low and did not differ between the groups. This study showed that nesiritide is safe when used in the emergency department, observation units, or similar settings.