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We report a case of ceftriaxone-induced encephalopathy correlated with high cerebrospinal fluid concentration. Neurotoxicity of cephalosporin is increasingly reported, especially regarding fourth-generation cephalosporins. The factors influencing the corticospinal fluid (CSF) concentration are plasma concentration, liposolubility, ionization, molecular weight, protein binding and efflux. In our patient, high levels of ceftriaxone (27.9 mg/l) were found in the CSF. β-lactam associated neurotoxicity is mainly related to similarities between GABA and β-lactam ring. Because of disparate CSF/plasma ratio and blood-brain barrier efflux among patients, plasmatic drug monitoring probably cannot be used as a surrogate of CSF concentration. This is, as we know, the first case of described ceftriaxone-induced encephalopathy associated with an objective excessive cerebrospinal concentration.