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High-dose paracetamol (6 g/day) is a low-cost intervention that may prevent pyrexia. The purpose of this study was to describe the pharmacokinetics of high-dose intravenous paracetamol, in patients with traumatic brain injury (TBI).A clinical pharmacokinetic study in adult patients with TBI was performed as a sub-study to a prospective, phase 2B, randomized placebo-controlled study (PARITY). Patients received 1 g of intravenous paracetamol or 0.9% sodium chloride every 4 h for 72 h.All patients were included in the pharmacokinetic sub-study. The mean age, weight and area under the concentration-time curve for the sampled dosing interval were 34.5 yr, 82.3 kg and 39.9 ± 19.8 mg.h/L, respectively. The concentrations observed in the study patients were well below the threshold of toxicity and there was no evidence of accumulation of paracetamol. Paracetamol clearance was found to be high and variable (25.7 L.h−1, coefficient of variation (CV) 40.9%), and a wide range of volume of distribution observed (27.6 L, CV 30.6%). A relationship between lower Glasgow coma scores and higher clearance of paracetamol was observed.Due to altered pharmacokinetics, patients experiencing severe TBI may require a higher dose of paracetamol to achieve drug exposure that results in preventing pyrexia.Highly variable volumes of distribution and clearance for IV paracetamol were observed.Lower Glasgow coma scores were associated with higher clearance of paracetamol.Paracetamol concentrations were below toxicity threshold with no evidence of accumulation.