Objective:　To　compare　the　acute　toxicity　and　chemical　ingredients　of　Psoraleae　Fructus　(PF)　with　those　of　two　classic　prescriptions,　Ershen　Wan　(ESW)　and　Sishen　Wan　(SSW).　Methods:　Based　on　classical　toxicological　methods,　body　weight,　food　and　water　consumption,　lethal　conditions,　and　toxic　reactions　were　recorded　after　administering　single　oral　doses　of　PF,　ESW,　and　SSW.　The　50%　lethal　dose　(LD50)　values　of　PF　and　ESW　and　the　maximum　tolerance　dose　(MTD)　of　SSW　were　determined.　In　addition,　PF,　ESW,　and　SSW　constituents　were　detected　using　ultra-high-performance　liquid　chromatography/mass　spectrometry　(UPLC-MS),　and　the　spectrum-toxicity　correlation　was　analyzed.　Results:　The　LD50　of　PF　and　ESW　were　53.9　g/kg/day　(46.2-63.0　g/kg/day,　95%　confidence　limit　[CL])　and　68.3　g/kg/day　(59.0-78.9　g/kg/day,　95%　CL),　which　were　respectively　about　40　and　50　times　the　human　daily　dosage.　The　MTD　of　SSW　was　41.0　g/kg/day,　indicating　the　highest　safety.　What　can　be　inferred　from　the　chemical　ingredients　and　toxicity　correlation　analyses　is　that　compatibility　reduced　the　contents　of　13　potential　hepatotoxin　compounds　in　PF.　Conclusions:　The　classic　compatibility　of　ESW　and　SSW　effectively　attenuated　the　hepatotoxicity　of　PF,　which　was　related　to　the　reduced　content　of　potentially　toxic　substances,　particularly　coumarins.　This　study　explored　the　principles　of　attenuating　the　toxicity　of　classic　prescriptions　to　provide　a　reference　for　the　rational　clinical　use　of　PF.　　Copyright　©　2024　Tianjin　University　of　Traditional　Chinese　Medicine.