Moxifloxacin is a fluoroquinolone with a broad spectrum of activity and good penetration into many tissues, including bone. Penetration of moxifloxacin into bone has not yet been studied using compartmental modeling techniques. Therefore, we determined the rate and extent of bone penetration by moxifloxacin and evaluated its pharmacodynamic profile in bone via Monte Carlo simulation. Twenty-four patients (10 males, 14 females) undergoing total hip replacement received 400 mg moxifloxacin orally 2 to 7 h prior to surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen by a cryogenic mill, including an internal standard. Drug concentrations were analyzed by high-performance liquid chromatography. We used ADAPT II (results reported), NONMEM, and WinBUGS for pharmacokinetic analysis. Monte Carlo simulation was performed to reverse engineer the necessary area under the free concentration-time curve fAUCSERUM/MIC in serum and total AUCBONE/MIC in bone for a successful clinical or microbiological outcome. The median (10 to 90 percentile for between-subject variability) of the AUC in bone divided by the AUC in serum (AUCBONE/AUCSERUM) was 80 (51 to 126 ) for cortical bone and 78 (42 to 144 ) for cancellous bone. Equilibration between serum and bone was rapid. Moxifloxacin achieved robust (Y90 ) probabilities of target attainment (PTAs) in serum, cortical bone, and cancellous bone up to MICs of 0.375 mg/liter based on the targets fAUCSERUM/MIC Y 40 and AUCBONE/MIC Y 33. Moxifloxacin showed high bone concentrations and a rapid equilibrium between bone and serum. The favorable PTAs compared to the 90 -inhibitory MIC of Staphylococcus aureus warrant future clinical trials on the effectiveness of moxifloxacin in the treatment of bone infections.