We compared two de-escalation strategies guided by either extravascular lung water or global end-diastolic volume-oriented algorithms in patients with sepsis and ARDS. Sixty patients with sepsis and ARDS were randomized to receive de-escalation fluid therapy, guided either by the extravascular lung water index (EVLWI,n= 30) or the global end-diastolic volume index (GEDVI,n= 30). In cases of GEDVI > 650 mL/m2or EVLWI > 10 mL/kg, diuretics and/or controlled ultrafiltration were administered to achieve the cumulative 48-h fluid balance in the range of 0 to −3000 mL. During 48 h of goal-directed de-escalation therapy, we observed a decrease in the SOFA score (p< 0.05). Extravascular lung water decreased only in the EVLWI-oriented group (p <0.001). In parallel, PaO2/FiO2increased by 30% in the EVLWI group and by 15% in the GEDVI group (p <0.05). The patients with direct ARDS demonstrated better responses to dehydration therapy concerning arterial oxygenation and lung fluid balance. In sepsis-induced ARDS, both fluid management strategies, based either on GEDVI or EVLWI, improved arterial oxygenation and attenuated organ dysfunction. The de-escalation therapy was more efficient for direct ARDS.