A simple, sensitive, and reliable high-performance liquid chromatographic (HPLC) method coupled with tandem mass spectrometry via electrospray ionization (ESI) source (LC-MS/MS) has been developed and validated for the simultaneous determination of five fluoroquinolone residues in milk. The studied fluoroquinolones were norfloxacin, ciprofloxacin, ofloxacin, enrofloxacin, and rufloxacin. The method involved a single solid-phase extraction (SPE) on C(18) followed by the analysis of all fluoroquinolones in a single chromatographic run using LC-ESI-MS/MS. Lomefloxacin was employed as the internal standard (IS). The limit of quantification (LOQ) was 0.5 ng/g in milk, much lower than the maximum residue limit (MRL) of 100 ng/g of enrofloxacin established by the Ministry of Agriculture of China. Standard curves were linear (r > 0.99) over the concentration range of 0.5-200 ng/g with good accuracy and precision. The method has been successfully applied to the analysis of 22 different brands of cow's milk on the Chinese market.