Objective To determine the effects of early de-escalation application of norepinephrine (NE) on the performance of early goal-directed therapy (EGDT) and its prognosis in the treatment of septic shock patients. Methods A total of 60 patients with identified septic shock who required NE treatment in our intensive care unit from January 2011 to March 2013 were enrolled in this study. They were randomly divided into 2 groups, with 30 patients in each group. Ultimately, there were 21 patients in each group after 18 cases of death or complicated with cardiogenic shock within 24h were excluded. The 2 groups were treated according to the EGDT target fluid resuscitation. The patients in first group underwent of conventional NE therapy (CNE group), with the dose of NE increased gradually till hemodynamics were stable. The patients in second group were given de-escalation application of norepinephrine(DNE group), that was NE at 0.5 or 1μg/(kg·min) firstly till hemodynamic stabilization, and then followed by de-escalation therapy. All the shock patients were scored using Acute Physiology And Chronic Health EvaluationⅡ (APACHEⅡ) scoring system before treatment. The heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), blood lactate, and central venous oxygen saturation (ScVO2) were recorded at the beginning and at 30 min, and 2, 6, 12 and 24h after the treatment of NE. At the same time, the amount of 24-hour fluid replacement, the incidences of acute kidney injury(AKI) and acute respiratory distress syndrome(ARDS), continuous renal replacement therapy (CRRT), decrease in blood pressure and stress ulcer after sedative drugs, and death within 28d were compared between the 2 groups. Results All patients achieved EGDT targets. MAP [(72.3±5.5) and (71.9±6.1)mmHg] and CVP [(10.3±1.9) and (10.5±1.8)mmHg] at 30 min and 2h respectively after treatment in DNE group were significantly higher than those in CNE group [(61.0±6.8) and (66.1±6.2)mmHg, (8.5±2.4) and (8.7±2.2)mmHg, all P＜0.05]. There was no significant difference in MAP and CVP at other time points between 2 groups (P＞0.05). Neither was the HR, blood lactate, and ScVO2 between the 2 groups at all time points (P＞0.05). The amount of 24-hour fluid replacement was lower in DNE group than in CNE group [(5708±934) vs (6352±1208)ml, P＜0.05]. There were less patients with lower blood pressure after sedative drugs in DNE group than in CNE group (6 vs 15, P＜0.05). The incidences of AKI, ARDS, stress ulcer, CRRT, and the mortality within 28 days had no significant difference between 2 groups (P＞0.05). Conclusion The de-escalation application of NE is more convenient for EGDT in treatment of septic shock, which does not increase the risk of ischemia in the important organs and is helpful to control the fluid resuscitation.