Objectives: We investigated the effects of nesiritide (NES) on inflammatory response during cardiac surgery. Materials and Methods: Twenty‑ nine cardiac surgery patients were randomized to an infusion of NES at 0. 01 mcg/kg/min for 48 h versus placebo (Ctrl). A panel of candidate biomarkers and clinical parameters were measured at predetermined time points. Results: There were no significant differences between the groups with regard to urine neutrophil gelatinase‑ associated lipocalin (NES 230. 3 + 71. 5 ng/mL vs. Ctrl 554. 4 + 263. 3 ng/mL, P = 0. 253) and urine interleukin (IL)‑ 18 (NES 29. 9 + 4. 8 pg/mL vs. 254. 5 + 118. 3 pg/mL, P = 0. 090), or to the incidence of acute kidney injury (NES 7. 1% vs. Ctrl 13. 3%, P = 0. 374). A concerted biomarker kinetic pattern of time‑ differentiated peak concentrations was observed. IL‑ 10, inflammatory protein (IP)‑ 10, IL‑ 6, IL‑ 10, IP‑ 10, monocyte IP (MIP)‑ 1α , interferon (IFN)‑ α , IFN‑ α , IL‑ 1a, IL‑ 3, and IL‑ 7 reached peak concentration at 0 h following the end of cardiopulmonary bypass; tumor necrosis factor (TNF)‑ α , endothelial growth factor (EGF), granulocyte macrophage‑ colony‑ stimulating factor (GM‑ CSF), IL‑ 12p40, IL‑ 17, MIP‑ 1α , and monocyte chemoattractant protein‑ 1 at 1 h; IL‑ 18, vascular EGF (VEGF), IL-13 and IL-1ra at 2 h, TNF-α , G-CSF, IL-1b, IL-2, IL-4, IL-5, and IL-15 at 4 h; and endothelin (ET)-1 and IL-18 at 6 h. At 0 h, the NES group exhibited significant reduction of peak concentrations of IL‑ 6 (P = 0. 009), IL‑ 10 (P = 0. 009), IL‑ 1α (P = 0. 020), IP‑ 10 (P = 0. 001), and IFN‑ α (P = 0. 032) compared to the Ctrl group. Significant reduction in peak concentrations of TNF‑ α (P = 0. 007) and MIP1‑ α (P = 0. 027) at 1 h and ET‑ 1 (P = 0. 020) at 6 h in the NES group compared to the Ctrl group was noted. Conclusion: NES modulated the concerted inflammatory response in cardiac surgery and also attenuated ET‑ 1 response, thus suggesting that previously observed favorable renal effect may be linked to reduced renal vasoconstriction.