OBJECTIVES: We examined the association between fluid overload and major adverse kidney events in critically ill patients requiring continuous renal replacement therapy for acute kidney injury. DESIGN: Retrospective cohort study. SETTING: ICU in a tertiary medical center. PATIENTS: Four-hundred eighty-one critically ill adults requiring continuous renal replacement therapy for acute kidney injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fluid overload was assessed as fluid balance from admission to continuous renal replacement therapy initiation, adjusted for body weight. Major adverse kidney events were defined as a composite of mortality, renal replacement therapy-dependence or inability to recover 50% of baseline estimated glomerular filtration rate (if not on renal replacement therapy) evaluated up to 90 days after discharge. Patients with fluid overload less than or equal to 10% were less likely to experience major adverse kidney events than those with fluid overload greater than 10% (71.6% vs 79.4%; p = 0.047). Multivariable logistic regression showed that fluid overload greater than 10% was associated with a 58% increased odds of major adverse kidney events (p = 0.046), even after adjusting for timing of continuous renal replacement therapy initiation. There was also a 2.7% increased odds of major adverse kidney events for every 1 day increase from ICU admission to continuous renal replacement therapy initiation (p = 0.024). Fluid overload greater than 10% was also found to be independently associated with an 82% increased odds of hospital mortality (p = 0.004) and 2.5 fewer ventilator-free days (p = 0.044), compared with fluid overload less than or equal to 10%. CONCLUSIONS: In critically ill patients with acute kidney injury requiring continuous renal replacement therapy, greater than 10% fluid overload was associated with higher risk of 90-day major adverse kidney events, including mortality and decreased renal recovery. Increased time between ICU admission and continuous renal replacement therapy initiation was also associated with decreased renal recovery. Fluid overload represents a potentially modifiable risk factor, independent of timing of continuous renal replacement therapy initiation, that should be further examined in interventional studies.