In vitro levofloxacin exhibits both potent or intermediate activity against most of the pathogens frequently responsible for acute bacterial meningitis and synergistic activity with some beta-lactams. Since levofloxacin was shown to penetrate the cerebrospinal fluid (CSF) during meningeal inflammation both in animals and in humans, the disposition of levofloxacin in CSF was studied in 10 inpatients with external ventriculostomy because of communicating hydrocephalus related to subarachnoid occlusion due to cerebral accidents who were treated with 500 mg of levofloxacin intravenously twice a day because of extracerebral infections. Plasma and CSF concentration-time profiles and pharmacokinetics were assessed at steady state. Plasma and CSF levofloxacin concentrations were analyzed by high-pressure liquid chromatography. The peak concentration of levofloxacin at steady state (Cmax ss)was 10.45 mg/liter in plasma and 4.06 mg/liter in CSF, respectively, with the ratio of the Cmax ss in CSF to the Cmax ss in plasma being 0.47. The areas under the concentration-time curves during the 12-h dosing interval (AUC0-τs) were 47.69 mg · h/liter for plasma and 33.42 mg · h/liter for CSF, with the ratio of the AUC0-τ for CSF to the AUC0-τ for plasma being 0.71. The terminal-phase half-life of levofloxacin in CSF was longer than that in plasma (7.02 ± 1.57 and 5.51 ± 1.36 h, respectively; P = 0.034). The ratio of the levofloxacin concentration in CSF to the concentration in plasma progressively increased with time, from 0.30 immediately after dosing to 0.99 at the end of the dosing interval. In the ventricular CSF of patients with uninflamed meninges, levofloxacin was shown to provide optimal exposure, which approximately corresponded to the level of exposure of the unbound drug in plasma. The findings provide support for trials of levofloxacin with twice-daily dosing in combination with a reference beta-lactam for the treatment of bacterial meningitis in adults. This cotreatment could be useful both for overcoming Streptococcus pneumoniae resistance and for enabling optimal exposure of the CSF to at least one antibacterial agent for the overall treatment period.