Background: Prediction of successful discontinuation of continuous renal replacement therapy (CRRT) might reduce complications of over- and under-treatment. The aim of this study was to identify renal and non-renal predictors of short-term successful discontinuation of CRRT in patients in whom CRRT was stopped because renal recovery was expected and who were still in the Intensive Care Unit (ICU) at day 2 after stop CRRT. Methods: Prospective multicentre observational study in 92 patients alive after discontinuation of CRRT for acute kidney injury (AKI), still in the ICU and free from renal replacement therapy (RRT) at day 2 after discontinuation. Successful discontinuation was defined as alive and free from RRT at day 7 after stop CRRT. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and clinical variables were collected. Logistic regression and Receiver Operator Characteristic (ROC) curve analysis were performed to determine the best predictive and discriminative variables. Results: Discontinuation of CRRT was successful in 61/92 patients (66%). Patients with successful discontinuation of CRRT had higher day 2 urine output, better renal function indicated by higher creatinine clearance (6-h) or lower creatinine ratio (day 2/day 0), less often vasopressors, lower urinary NGAL, shorter duration of CRRT and lower cumulative fluid balance (day 0-2). In multivariate analysis renal function determined by creatinine clearance (Odds Ratio (OR) 1.066, 95% confidence interval (CI) 1.022-1.111, p = 0.003) or by creatinine ratio (day 2/day 0) (OR 0.149, 95% CI 0.037-0.583, p = 0.006) and non-renal sequential organ failure assessment (SOFA) score (OR 0.822, 95% CI 0.678-0.996, p = 0.045) were independently associated with successful discontinuation of CRRT. The area under the curve of creatinine clearance to predict successful discontinuation was 0.791, optimal cut-off of 11 ml/min (95% CI 6-16 ml/min) and of creatinine ratio 0.819 (95% CI 0.732-0.907) optimal cut-off of 1.41 (95% CI 1.27-1.59). Conclusion: In this prospective multicentre study we found higher creatinine clearance or lower creatinine ratio as best predictors of short-term successful discontinuation of CRRT, with a creatinine ratio of 1.41 (95% CI 1.27-1.59) as optimal cut-off. This study provides a practical bedside tool for clinical decision making.