The optimal timing for initiating continuous renal replacement therapy (CRRT) remains controversial, and it is not obvious which parameters should be considered during this process. We investigated the predictive value of physiological parameters among critically ill patients receiving CRRT due to acute kidney injury (AKI). A total of 496 patients who started CRRT were prospectively enrolled. The following physiological parameters were significantly associated with mortality even after multivariate adjustments: level of pH [hazard ratio (95% CI): 7.15 < pH ≤ 7.20, 1.971 (1.319-2.946); pH ≤ 7.15, 2.315 (1.586-3.380); reference > 7.25, P-for-trend < 0.001]; bicarbonate level (HCO3(-)) [≤ 14 mmol/L, 2.010 (1.542-2.620); reference > 18 mmol/L, P-for-trend < 0.001]; phosphorus level [> 7 mmol/L, 1.736 (1.313-2.296); reference ≤ 5 mmol/L, P-for-trend < 0.001]; and urine output < 0.3 ml/kg/hr [1.509 (1.191-1.912); reference > 0.3 ml/kg/hour]. Weight gain over 2 kg was associated with mortality exclusively according to univariate analysis [1.516 (1.215-1.892)]. The diagnostic value of the composite of these factors (pH, bicarbonate level, phosphorus level, urine output, weight gain, and potassium levels) [area under the curve (AUC) 0.701, 95% CI 0.644-0.759] was comparable to or higher than the blood urea nitrogen level (AUC 0.571, 95% CI 0.511-0.630), serum creatinine level (AUC 0.462, 95% CI 0.399-0.525), eGFR (AUC 0.541, 95% CI 0.478-0.605), and AKI Network stage (AUC 0.627, 95% CI 0.561-0.692). In conclusion, the physiological parameters are useful in predicting post-AKI mortality and should be considered when initiating CRRT in critically ill patients with AKI.