Background: Fluid balance and oliguria influence outcome in critically ill patients. Although, osmotic dieresis with hypernatraemia is a predictor of mortality in critically ill patients, the purpose of this study was to demonstrate the effect of polyuria as an independent predictor on weaning outcome in mechanically ventilated patients. Materials and Methods: This retrospective, single center, cohort study was carried out at Imam Teaching Hospital Intensive Care Unit (ICU) on 263 adult mechanically ventilated patients. We collected data of these patients during the mean seven consecutive days before weaning from mechanical ventilator. Patients with polyuria (sustained urine output greater than 3000 ml/day) were compared with patients without polyuria. The primary endpoint was successful weaning and the secondary endpoints were the mechanical ventilation duration, post weaning length of ICU stay, post weaning length of hospitalization and rate of mortality. Results: In 93 patients with polyuria, the mean age was 45.14±19.47 years in comparison of 170 patients without polyuria with mean age of 52.9±21.37 years (P=0.004). Fluid intake, urine output and temperature were significantly higher in patients with polyuria, but there were no statistical differences in systolic and diastolic blood pressure, serum electrolytes, urea and creatinine. No significant differences were found in primary and secondary endpoints including successful weaning, post weaning length of ICU stay, post weaning hospital duration and mortality, except for duration of mechanical ventilation (P=0.014). The area under the ROC curve for variables showed only seven days mean creatinine level before weaning which may act as a predictor of successful weaning (ROCAUC=0.67, 95% CI 0.61-0.73, P=0.0002). Serum creatinine level of 0.8 provided best overall combination of sensitivity and specificity for successful weaning (sensitivity 72.22%, 95% CI 54.8-85.8; specificity 61.19%, 95% CI 54.1-68.0). Conclusion: Polyuria cannot predict weaning outcome but maybe considered as a predictor of longer duration of mechanical ventilation and is probably associated with a subclinical renal dysfunction.