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Background: Intravenous fluid therapy is one of the most common interventions in critically ill patients. Normal saline is frequently used, but there have been some concerns about hyperchloremia. Due to closer to plasma composition, crystalloids have been used as alternatives to normal saline. However, the optimal choice of resuscitative fluids remains controversial. Methods: MEDLINE, EMBASE, and CENTRAL were comprehensively searched until July 2021 to compare balanced crystalloids with normal saline in critically ill patients with the risk factors for multiple organ dysfunction syndromes (MODS).The primary endpoint was composite mortality. Secondary outcomes were acute kidney injury (AKI)/acute renal failure (ARF), and new receipt of renal replacement therapy (RRT). Results: A total of 1,240 studies were searched, and finally, 8 randomized controlled trials and 5 cohort studies were included. In the meta-analysis of composite mortality of 30,710 patients, balanced crystalloids compared to normal saline were significantly associated with reduced mortality (OR 0.80, 95% CI 0.68-0.95). In AKI/ARF, balanced crystalloids had a lower risk than normal saline (OR 0.91, 95% CI 0.84-0.99). There was no difference between balanced crystalloids and normal saline in risk of new receipt of RRT (OR 0.91, 95% CI 0.80-1.04). Conclusion: In fluid resuscitation for patients at high risk of MODS, the use of balanced crystalloids showed a significantly lower incidence of mortality compared to normal saline.