Adulteration in herbal medicines (HMS) and food sample (FS) is one of the challenging problems that are associated with manufacturing of HMs and FS. Therefore, the development of rapid method for the determination of common adulterants in HM and FS is a great importance. In this study, a fülly validated High Performance Liquid Chromatography coupled to Tandem Mass Spectrometry (HPLC-MS/MS) method was developed for qualitative and quantitative analysis of six synthetic adulterants, namely várdenafil, phenolphthalein, sildenafil, yohimbine, prednisolone and hydrocortisone hemisuccinate. The separation method was developed and optimized to achieve optimum separation and response of six synthetic drugs. The two columns were evaluated, monolithic analytical column (Chromolith®FastGradient RP-18e , 50-2 mm, Germany) and poroshell 120 EC C18 column (2.7um particle, 3.0x50 mm). Rapid separation was achieved on monoithic column using 70 % solvents A (10 mMol L ammonium formate , pH= 2.5) and 30 % solvent B (20 % ACN& 10 % MeOH) as mobile phase at a flow rate of 1.5 ml min-' with a simple gradient program. Qualitative and quantitative analysis of the adulterants were accomplished using tandem ESI-MS. Good linearity was found over a concentration range between 0.1 to 500 ng ml- for yohimbine and 50 to 500 ng ml•lfor sildenafil and hydrocortisone hemisuccinate with correlation coefficients over the range of 0.9901–0.9983. The LOD of six synthetic adulterants ranged from 0.019 to 5.11 ng mL-1. The method has been successfully applied to the analysis of samples of natural dietary supplements. Results showed that six samples were adulterated among the 25 screened.