A method was established for the determination of 61 central nervous system drugs in plasma by using protein precipitation combined with high performance liquid chromatography-diode array detection (HPLC-DAD). A volume of 1.5 mL acetonitrile was added into 1 mL plasma, after vortex, centrifugation and filtration, the supernatant was directly injected into HPLC. The separation was performed on an Agilent TC-C18 column (250 mm x 4.6 mm, 5 microm) with acetonitrile and phosphate buffer solution as mobile phase by gradient elution at a flow rate of 1.5 mL/min. The detection wavelength was 210 nm; full spectra were recorded from 200-364 nm. The recoveries of 61 drugs were larger than 80% with the relative standard deviations (RSDs) ranged from 0.94% to 11.23%. The protein precipitation method is simple, rapid, low-cost with good recoveries, reproducibility and suitable for the general pretreatment of the systematic toxicological analysis (STA) of the 61 drugs.