Abstract: Objective: To investigate the effects of early 6-hour fluid resuscitation and 24-hour cumulative fluid balance on 28-day mortality in patients with septic shock, and to evaluate their potential interaction. Methods: This single-center retrospective cohort study included 291 patients with septic shock. Patients were stratified based on early 6-hour fluid resuscitation volume (using 30 mL/kg as the cutoff) and 24-hour cumulative fluid balance (using the median of 35.83 mL/kg as the cutoff). Both two-group and four-group models were constructed. Multivariable logistic regression model was performed to analyze the associations between these fluid management indicators and 28-day mortality, followed by survival analysis. Results: The 28-day mortality rate in patients with septic shock was 43.3%. Multivariate logistic analysis showed that a high 24-hour cumulative fluid balance was significantly associated with 28-day mortality (OR=2.33, 95% CI: 1.21-4.46, P=0.011), whereas early 6-hour fluid resuscitation volume did not demonstrate an independent predictive effect after multivariable adjustment. Further subgroup analysis revealed that patients in the high resuscitation-high balance group had the highest risk of death (OR=2.77, 95% CI: 1.28-5.99, P=0.010), while prognosis in the high resuscitation-low balance group (OR=1.02, 95% CI: 0.40-2.63, P=0.965) was comparable to that in the low resuscitation-low balance reference group. Survival analysis yielded results consistent with these findings. Conclusion: In patients with septic shock, compared with early 6-hour fluid resuscitation volume, 24-hour cumulative fluid balance demonstrated more consistent risk stratification performance in stratified analyses, and the effect of early fluid resuscitation on mortality may be modified by subsequent fluid management strategies. Fluid therapy strategies in patients with septic shock should shift from simply emphasizing the initial resuscitation volume to focusing on dynamic, whole-course volume management.