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Background: Piperacillin/Tazobactam is frequently used for empirical treatment in patients with sepsis. Pathophysiological changes during the early phase of sepsis have significant effects on pharmacokinetic/pharmacodynamic (PK/PD) behaviors. This study aimed to characterize the population PKs of piperacillin and investigate probability of target attainment (PTA) and cumulative fraction of response (CFR) of various dosage regimens in critically ill patients during the early phase of sepsis. Methods: Forty-eight patients treated with piperacillin/tazobactam were recruited. Five blood samples were drawn before and during 0-0.5, 0.5-2, 2-4 and 4-6 or 8 hours after administration. Free piperacillin concentrations were determined using HPLC. Population PKs was analyzed using NONMEM®. The PTA of 90%fT>MIC target and CFR were determined by Monte Carlo simulation. Results: The two compartment model best described the data. Piperacillin clearance (CL), central volume of distribution (V1) and peripheral volume of distribution were 5.37 L/h, 9.35 L, and 7.77 L, respectively. Creatinine clearance (CLCr) and mean arterial pressure had a significant effect on CL while adjusted body weight had a significant impact on V1. The standard regimen, 4-g of piperacillin infused over 0.5 hours every 6 hours, achieved the target for susceptible organisms with MIC ≤16 mg/L in patients with CLCr 10 to 40 ml/min, but not with CLCr 40-120 ml/min. In such patients, prolonged infusion is required. Most regimens provided CFR 90% for the E. coli infection while there was no dosage regimen achieved a CFR of 90% for the P. aeruginosa infection. Conclusions: Due to high CL and V1, subtherapeutic concentrations can occur during the early phase of sepsis in critically ill patients with normal renal function. Our proposed regimen for the patients with CLCr 40-120 ml/min was an extended 4-hour infusion of 4-g of piperacillin every 6 hours.