A common approach to assess the efficacy of piperacillin is to firstly measure the total concentration, and to afterwards apply a theoretical unbound fraction of 70% to obtain the unbound concentration. However, hypoalbuminemia is a common phenomenon in critically ill patients, resulting in variations in unbound fraction. Therefore, we aimed to simulate the impact of piperacillin unbound fraction fluctuations on the predictive performance of a population pharmacokinetic model and on dosing recommendations of piperacillin. Unbound factors of 70, 75, 80 and 85% were applied to total concentrations of piperacillin administered by continuous infusion from an external dataset. A validated model was used for assessment of predictive performance and to estimate patient clearance. Dosing simulations were performed to evaluate target attainment. Variation in unbound fraction caused minimal impact on piperacillin clearance and target attainment but revealed to influence model evaluation.