For a study, researchers sought to determine optimal dosing regimens by describing the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients. About 2 pharmacokinetic investigations and a therapeutic drug monitoring (TDM) program at a tertiary hospital intensive care unit yielded a total and unbound ceftriaxone concentrations. Pmetrics for R was used to determine the chance of reaching a free trough concentration/MIC ratio of 1 or more than that using population pharmacokinetic analysis and Monte Carlo simulations. About 36 patients provided 474 samples (267 total and 207 unbound). The data were best explained by a 2-compartment model depicting ceftriaxone-albumin binding with both nonrenal and renal elimination and included creatinine clearance to account for between-patient variability. Across different dosage regimens and simulated creatinine clearances, an albumin concentration of less than or equal to 20 g/L reduced the probability of target attainment (PTA) by up to 20%. Patients with a creatinine clearance of less than 100 mL/min infected with sensitive isolates (PTA, ~90%) were likely to benefit from a ceftriaxone treatment of 1g twice daily. Patients with enhanced renal clearance (creatinine clearance, >130mL/min) who were infected with pathogens with MICs of more than or equal to 0.5 mg/L require higher dosages delivered as a continuous infusion (4g/day). The dose of ceftriaxone should be determined by the patient’s renal function, albumin content, and isolate MIC.