A method for the determination of sertraline, a new antidepressant drug and a selective serotonin reuptake inhibitor (SSRI), in human plasma is described. Therapeutic drug monitoring (TDM) necessitates efficient, fast and reliable analytical methods validated by external quality control. We therefore devised a simple, rapid and sensitive isocratic reversed-phase liquid chromatographic-tandem mass spectrometric method equipped with Turbo Ion spray (TIS) source, operating in the positive ion and selective reaction monitoring (SRM) acquisition mode to quantify sertraline in human plasma. A new and superior procedure of solid-phase extraction (SPE) (compared to liquid-liquid extraction) was followed to extract sertraline and imipramine as internal standard (IS) from the human plasma. Sample preparation was performed using waters hydrophilic-lipophilic balance (HLB) cartridge and this method yielded extremely clean extracts with very good recovery, 81.47 and 85.79% for sertraline and IS, respectively. Both were analyzed by combined reverse phase liquid chromatography and tandem mass spectrometry (LC-MS/MS) with positive ion TIS ionization using SRM acquisition mode. The response of the LC-MS/MS method for sertraline was linear over the dynamic range of 0.5-60.0 ng/ml with correlation coefficient r>or=0.9996. The coefficient of variance (%CV) was 8.53% at 0.5 ng/ml and the accuracy was well within the accepted limit of +/-20% at lower limit of quantification (LLOQ) and +/-15% at all the other concentrations in the linear range. This method was fully validated for the accuracy, precision and stability studies. The above findings indicate that the method is very much accurate and precise and can be successfully applied for bioequivalence studies in human subjects.