This study investigated fluid removal strategies for critically ill patients with fluid overload on mechanical ventilation. Traditionally, a negative fluid balance (FB) is aimed for. However, this approach can have drawbacks. Here, we compared a new approach, namely removing fluids until patients become fluid responsive (FR) to the traditional empiric negative balance approach. Twelve patients were placed in each group (n = 24). FR assessment was performed using passive leg raising (PLR). Both groups maintained stable blood pressure and heart function during fluid management. Notably, the FR group weaned from the ventilator significantly faster than negative FB group (both for a spontaneous breathing trial (14 h vs. 36 h, p = 0.031) and extubation (26 h vs. 57 h, p = 0.007); the difference in total ventilator time wasn't statistically significant (49 h vs. 62 h, p = 0.065). Additionally, FR group avoided metabolic problems like secondary alkalosis and potential hypokalemia seen in the negative FB group. FR-guided fluid-removal in fluid overloaded mechanically ventilated patients was a feasible, safe, and maybe superior strategy in facilitating weaning and disconnection from mechanical ventilation than negative FB-driven fluid removal. FR is a safe endpoint for optimizing cardiac function and preventing adverse consequences during fluid removal.