Moxifloxacin, an 8-methoxyquinolone with broad-spectrum activity in vitro, was studied in the rabbit model of Escherichia coli meningitis. The purposes of this study were to evaluate the bactericidal effectiveness and the pharmacodynamic profile of moxifloxacin in cerebrospinal fluid (CSF) and to compare the bactericidal activity with that of ceftriaxone and meropenem therapy. After induction of meningitis, animals were given single doses of 10, 20, and 40 mg/kg or divided-dose regimens of 5, 10, and 20 mg/kg twice, separated by 6 h. After single doses, the penetration of moxifloxacin into purulent CSF, measured as percentage of the area under the concentration-time curve (AUC) in CSF relative to the AUC in plasma, was approximately 50%. After single doses of 10, 20, and 40 mg/kg, the maximum CSF concentration (C_max) values were 1.8, 4.2, and 4.9 µg/ml, respectively; the AUC values (total drug) were 13.4, 25.4, and 27.1 µg/ml · h, respectively, and the half-life values (t_1/2) were 6.7, 6.6, and 4.7 h, respectively. The bacterial killing in CSF for moxifloxacin, calculated as the log₁₀ CFU per milliliter per hour, at 3, 6, and 12 h after single doses of 10, 20, and 40 mg/kg were 5.70, 6.62, and 7.02; 7.37, 7.37, and 6.87; and 6.62, 6.62, and 6.62, respectively, whereas those of ceftriaxone and meropenem were 4.18, 5.24, and 4.43, and 3.64, 3.59, and 4.12, respectively. The CSF pharmacodynamic indices of AUC/MBC and C_max/MBC were interrelated (r = 0.81); there was less correlation with T > MBC (r = 0.74). In this model, therapy with moxifloxacin appears to be at least as effective as ceftriaxone and more effective than meropenem therapy in eradicating E. coli from CSF.