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Background: Hypophosphatemia in critically ill patients is a common electrolyte disturbance associated with a myriad of adverse effects. Critically ill patients requiring continuous renal replacement therapy (CRRT) are at high risk of hypophosphatemia and often require phosphate supplementation during therapy. The aim of this study was to evaluate the association of phosphate versus non-phosphate containing CRRT solutions with incident hypophosphatemia in critically ill patients requiring CRRT. Materials and Methods: This is a single-center, retrospective, cohort study at a tertiary academic medical center of 1,396 adult patients requiring CRRT during their intensive care unit stay comprising 7,529 (phosphate containing) and 4,821 (non-phosphate containing) cumulative days of CRRT. Multivariable logistic regression was used to model the primary outcome of hypophosphatemia during CRRT according to exposure to phosphate versus non-phosphate containing CRRT solutions. Results: Incident hypophosphatemia during CRRT, serum phosphate <2.5 mg/dL or 0.81 mmol/L, was significantly higher in the non-phosphate versus phosphate containing solution group: 304/489 (62%) versus 175/853 (21%) (p < 0.001). Cumulative phosphate supplementation was also significantly higher in the non-phosphate versus phosphate containing solution group: 79 (IQR: 0–320) versus 0 (0–16) mmol (p < 0.001). Non-phosphate solutions were associated with an 8-fold increase in the incidence of hypophosphatemia (adjusted OR 8.05; 95% CI 5.77, 11.26; p < 0.001). Discussion/Conclusions: The use of phosphate containing CRRT solutions was independently associated with reduced risk of incident hypophosphatemia and decreased phosphate supplementation during CRRT. Interventional studies to confirm these findings are needed.