BACKGROUND Levetiracetam (LEV) is widely used in the clinical monotherapy or multi-drug combination treatment of seizures due to its good tolerability and efficacy. Due to a lack of large-scale clinical studies, the relationship between levetiracetam concentrations, disease activity and adverse is unclear, limiting the usefulness of therapeutic drug monitoring (TDM) based LEV plasma levels. This study was intended to investigate factors influencing the pharmacokinetics of and the appropriate reference range of LEV concentration using available LEV TDM data. METHODS A rapid, accurate and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) method was established to determine LEV plasma concentrations. In this study, the levetiracetam plasma concentration monitoring data from 352 samples (taken from 248 patients) were used to explore the relationship between levetiracetam dose, age, combined administration with other antiseizure medications in patients with epilepsy. RESULTS Age and combined administration emerged as important affecting factors for the correlation of LEV concentration and dose. The correlation between concentration and dose was better in monotherapy. Combined administration may affect LEV concentration, especially when LEV is combined with oxcarbazepine, which might decrease the LEV concentration. CONCLUSIONS These findings emphasize the need to monitor LEV routinely LEV, especially among children and older adults when other antiseizure comedications are prescribed in the treatment regimen. LEV TDM is a well-established tool for the management of patients with epilepsy.