An HPLC method with a fluorescence detector (HPLC-FLD) was described for the quantitative determination of closantel and rafoxanide in bovine and ovine muscles. A structural analog closely related to rafoxanide, viz., N-[4-(4-chlorophenoxy) phenyl]-2-hydroxy-3,5-diiodobenzamide, was synthesized as an internal standard. Bovine and ovine muscles were extracted with acetonitrileacetone (60 + 40, v/v) followed by cleanup on mixed mode anionic exchange SPE cartridges. After evaporation and reconstitution with the mobile phase, the sample was analyzed by HPLC-FLD using internal standard calibration. The method was validated by using fortified bovine and ovine muscles at 15, 30, and 60 µg/kg. The accuracy and RSD were 70110% and 10%, respectively.