A unique, easy, precise and exact high-performance liquid chromatographic-mass tandem (LCMS/MS) approach was created and validated for the measurement of the antihypertensive medicine Lisinopril (LIS) in dried blood spots (DBS). This was the first time according to our knowledge that LIS is being validated in DBS. Liquid chromatography mass tandem was utilized using the Water Acquity column as UPLC -HSS T3® column. Ten millimole ammonium formate, 0.2 percent formic acid, 0.2 percent trimethylamine, one percent acetonitrile (pH 3.0± 0.02) used as mobile phase (A) and a mobile phase (B) consisting of 0.2 percent formic acid in acetonitrile. The mobile phase lasts for 2.5 minutes at a flow rate of 0.2 ml/min. For the drug as well internal standard, the retention times (RT) obtained under optimal circumstances were 0.63±0.02 and 2.18±0.03 min, dried blood spot samples, offering consistent and quantitative drug recovery. The process was the shortest RT reported for the LIS, it is a linear relationship with concentrations from 10 - to 100ng/ml. A protein precipitation approach was used to measure the LIS. The method used to analyze DBS samples from rats receiving LIS.