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Background: Critically ill patients are at increased risk for fluid overload, but objective prediction tools to guide clinical decision-making are lacking. The MRC-ICU scoring tool is an objective tool for measuring medication regimen complexity. Objective: To evaluate the relationship between MRC-ICU score and fluid overload in critically ill patients. Methods: In this multi-center, retrospective, observational study, the relationship between MRC-ICU and the risk of fluid overload was examined. Patient demographics, fluid balance at day 3 of ICU admission, MRC-ICU score at 24 hours, and clinical outcomes were collected from the medical record. The primary outcome was relationship between MRC-ICU and fluid overload. To analyze this, MRC-ICU scores were divided into tertiles (low, moderate, high), and binary logistic regression was performed. Linear regression was performed to determine variables associated with positive fluid balance. Results: A total of 125 patients were included. The median MRC-ICU score at 24 hours of ICU admission for low, moderate, and high tertiles were 9, 15, and 21, respectively. For each point increase in MRC-ICU, a 13% increase in the likelihood of fluid overload was observed (OR 1.128, 95% CI 1.028-1.238, p = 0.011). The MRC-ICU score was positively associated with fluid balance at day 3 (β-coefficient 218.455, 95% CI 94.693-342.217, p = 0.001) when controlling for age, gender, and SOFA score. Conclusions: Medication regimen complexity demonstrated a weakly positive correlation with fluid overload in critically ill patients. Future studies are necessary to establish the MRC-ICU as a predictor to identify patients at risk of fluid overload.