In critically ill adults, does the use of balanced crystalloids improve clinical outcomes compared to normal saline for fluid resuscitation? This cluster-randomized, multiple-crossover trial enrolled 15,802 ICU patients across five US medical centers to evaluate the impact of balanced crystalloids (Lactated Ringer’s or Plasma-Lyte A) versus saline. The study demonstrated that balanced crystalloids significantly reduced the incidence of the composite outcome compared to saline, particularly in minimizing kidney injury and improving metabolic outcomes. There was no increase in adverse events in the balanced crystalloids group, highlighting their safety. These findings established balanced crystalloids as a preferred option over saline for fluid resuscitation in critically ill patients, influencing clinical guidelines and practice globally.