Background: Recent studies have suggested that early goal-directed resuscitation of patients with septic shock and conservative fluid management of patients with acute lung injury (ALI) can improve outcomes. Because these may be seen as potentially conflicting practices, we set out to determine the influence of fluid management on the outcomes of patients with septic shock complicated by ALI. Methods: A retrospective analysis was performed at Barnes-Jewish Hospital (St. Louis, MO) and in the medical ICU of Mayo Medical Center (Rochester, MN). Patients hospitalized with septic shock were enrolled into the study if they met the American-European Consensus definition of ALI within 72 h of septic shock onset. Adequate initial fluid resuscitation (AIFR) was defined as the administration of an initial fluid bolus of ≥ 20 mL/kg prior to and achievement of a central venous pressure of ≥ 8 mm Hg within 6 h after the onset of therapy with vasopressors. Conservative late fluid management (CLFM) was defined as even-to-negative fluid balance measured on at least 2 consecutive days during the first 7 days after septic shock onset. Results: The study cohort was made up of 212 patients with ALI complicating septic shock. Hospital mortality was statistically lowest for those achieving both AIFR and CLFM and higher for those achieving only CLFM, those achieving only AIFR, and those achieving neither (17 of 93 patients [18.3%] vs 13 of 31 patients [41.9%] vs 30 of 53 patients [56.6%] vs 27 of 35 [77.1%], respectively; p < 0.001). Conclusions: Both early and late fluid management of septic shock complicated by ALI can influence patient outcomes.