BACKGROUND: IV fl uid represents a basic therapeutic intervention for septic shock. Unfortunately, the optimal administration of IV fl uid to maximize patient outcomes and prevent complications is largely unknown. METHODS: Patients with septic shock admitted to the medical ICUs of Barnes-Jewish Hospital (January to December 2014) requiring vasoactive agents for at least 12 h following initial fl uid resuscitation were randomized to usual care or to targeted fl uid minimization (TFM) guided by daily assessments of fl uid responsiveness. RESULTS: Eighty-two patients were enrolled, 41 to usual care and 41 to TFM. For patients randomized to TFM, the net median (interquartile range) fl uid balance was less at the end of day 3 (1,952 mL [48-5,003 mL] vs 3,124 mL [767-10,103 mL], P 5.20) and at the end of day 5 (2,641 mL [2 1,837 to 5,075 mL] vs 3,616 mL [2 1,513 mL to 9,746 mL], P 5.40). TFM appeared to be safe, as indicated by similar clinical outcomes including in-hospital mortality (56.1% vs 48.8%, P 5.51), ventilator days (8.0 days [3.25-15.25 days] vs 5.0 days [3.0-9.0 days], P 5.30), renal replacement therapy (41.5% vs 39.0%, P 5.82), and vasopressor days (4.0 days [2.0-8.0 days] vs 4.0 days [2.0-6.0 days], P 5.84). CONCLUSIONS: Th is pilot study suggests that TFM in patients with septic shock can be performed using protocol-guided assessments of fl uid responsiveness. Larger trials of TFM in septic shock are needed.