Background: The weaning of vasopressors is usually an empirical choice made by clinicians. The aim of this study is to assess the predictive value of change in effective arterial elastance (ΔEa%) induced by fluid administration in early initiation of norepinephrine (NE) weaning. Methods: Included were intensive care unit (ICU) septic shock patients with an indwelling pulmonary artery catheter who experienced initial resuscitation and required a fluid challenge. Reduced norepinephrine dose or maintained steady (ΔNE ≤0 μg/min) at 6 hours after inclusion (T6) was defined as early initiation of norepinephrine weaning. Univariate and multivariate analyses were performed to assess ΔEa% viability and other hemodynamic parameters in predicting the possibility of norepinephrine weaning. A receiver operating characteristic (ROC) analysis was used to confirm model predictions. Results: One hundred and eight patients were assessed. Of 108 patients, 75 (69.4%) constituted the NE weaning group at T6. The multivariate analysis showed that ΔEa% [odds ratios (OR): 0.95; 95% confidence interval (CI): 0.89–0.99; P=0.003] was an independent predictive factor for norepinephrine weaning at T6. ROC analysis confirmed that ΔEa% was associated with norepinephrine weaning [area under ROC curve (AUC) at 0.64; 95% CI: 0.52–0.75; P=0.026]. To predict norepinephrine weaning, the optimum threshold for ΔEa% was 5.1% (sensitivity: 61%, specificity: 67%). Notably, the combination of ΔEa%, change in systemic vascular resistance (ΔSVR%) and change in cardiac output (ΔCO%) strengthened the predictive ability with an AUC at 0.73 (95% CI: 0.64–0.83; P=0.001). Median (interquartile range) duration (in hours) of norepinephrine was significantly shorter in the NE weaning group compared with the NE worsening group {48 [34–89] vs. 72 [54–90] hours, P=0.048}. Conclusions: Change in effective arterial elastance induced by fluid administration may assist clinicians in detecting patients who is possible to initiate norepinephrine weaning. Early initiation of norepinephrine weaning was associated with shorter duration of norepinephrine exposure.