BACKGROUND: Fluid management is crucial to acute respiratory distress syndrome (ARDS) secondary to sepsis. However, choices of fluid resuscitation strategies and fluid input volumes remain a thy problem. Our study aimed to elucidate the relationship between fluid balance and prognosis of ARDS patients secondary to sepsis. METHODS: Our study included 322 sepsis patients from Ruijin Hospital between 2014 and 2018, and 84 patients were diagnosed as ARDS within 72 hours after onset of sepsis according to Berlin ARDS Definition. RESULTS: Among the 322 sepsis patients, 84 (26.1％) were complicated with ARDS within 72 hours. ARDS patients had a lower oxygenation index (PaO2/FiO2166.4±71.0 vs. 255.0±91.2,P<0.05), longer duration of mechanical ventilation (11 [6–24] days vs. 0 [0–0] days,P<0.05) than those without ARDS. Sepsis patients with ARDS showed daily positive net fluid balance during seven days compared with those without ARDS who showed daily negative net fluid balance since the second day with significant statistical differences. Among the 84 sepsis patients with ARDS, 58 (69.0％) died. Mean daily fluid input volumes were much lower in survivors than in non-survivors (43.2±16.7 mL/kg vs. 51.0±25.2 mL/kg,P<0.05) while output volumes were much higher in survivors (45.2±19.8 mL/kg vs. 40.2±22.7 mL/kg,P<0.05). Using binary logistic regression analysis, we found that the mean daily fluid balance was independently associated with mortality of sepsis patients complicating with ARDS (P<0.05). CONCLUSIONS: Early negative fluid balance is independently associated with a better prognosis of sepsis patients complicated with ARDS.