This retrospective substudy of the Follow-Up Serial Infusions of Nesiritide trial (FUSION I) assessed the feasibility of outpatient administration of nesiritide in 138 patients with co-morbid advanced heart failure and renal insufficiency (estimated creatinine clearance<60 ml/min). Patients received 1 of 3 treatments once weekly for 12 weeks: standard care (SC), SC plus nesiritide 0.005 microg/kg/min, or SC plus nesiritide 0.010 microg/kg/min. The addition of nesiritide to SC was well tolerated, with no evidence of worsening renal function, compared with SC only and was associated with a reduction in the rate of all-cause hospitalization or mortality through week 12, with hazard ratios of 2.027 (95% confidence interval 1.165 to 3.525) and 2.219 (95% confidence interval 1.233 to 3.992) for the SC-only group compared with the SC plus 0.005 microg/kg/min and SC plus 0.010 microg/kg/min nesiritide groups, respectively. These findings raise the hypothesis that adjunctive therapy with nesiritide on an outpatient basis may be beneficial for patients with advanced heart failure and renal insufficiency. Further study is warranted to test the validity of this finding.