A simple, sensitive and rugged quantitative method for the determination of Clopidogrel in human plasma (K2EDTA) using liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated. Clopidogrel-d3 was used as an internal standard. Analyte and the internal standards were extracted from human plasma by liquid-liquid extraction technique using Methyl tertiary butyl ether as extraction solvent and 0.5% formic acid as extraction buffer. The reconstituted samples were chromatographed on a C18 column by using acetonitrile / 5mM ammonium acetate (90/10, V/V) as the mobile phase. The method was validated over the concentration range of 101.98–61028.96 pg/mL. The Quattro Premier XE mass spectrometry was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique for quantification of ion transitions at m/z 322.13/212.04 and 326.06/215.04 for the drug and the internal standard respectively. The results of the intra and inter batch precision and accuracy studies were well within the acceptable limits. The method has been proved to be simple, sensitive, fast, reliable, rugged and reproducible. A run time of 2.50 min for each sample made it possible to analyze more than 400 plasma samples per day. The proposed method can be applied for the estimation of the drug in real time plasma samples for pharmacokinetic studies. Key words: Clopidogrel, Validation, Human Plasma, LC-MS/MS, Electrospray ionization.