Determination of drugs in human plasma using the HPLC technique has been widely accepted as an effective method owing to its practical applicability in routine drug analysis in clinical trials. The method sensitivity can be compromised once limited sample volume is available. This problem is typically encountered in pharmacokinetics studies from which small volume of plasma samples either form humans or animals can be obtained. Atorvastatin, an HMG-CoA reductase inhibitor widely prescribed for the treatment of hypercholesterolemia and the prevention of cardiovascular diseases was selected as a model drug in this study. Drug extraction from human plasma was performed with the aid of reversed-phase C18 solid phase micro-extraction. The detection was accomplished by triple quandruple mass spectrometer interfaced operated in electrospray positive ion mode. Quantitation was achieved by using multiple reaction monitoring (MRM) precursor-production transitions at m/z 559.2 and 440.1 for atorvastatin and m/z 412.2 and 224.2 for fluvastatin (internal standard). Linearity was found within the atorvastatin concentration range of 0.2-80 ng/ml. The limit of detection was found to be 0.05 ng/ml. The lower limit of quantification was 0.2 ng/ml with a relative standard deviation (%RSD) of less than 12%. Acceptable precision and accuracy were obtained for the concentrations within the calibration curve range. The average recovery at low, medium and high of atorvastatin concentrations from spiked plasma: quality control samples, were 84.16 ± 7.99%, 96.82 ± 6.14%, and 102.84 ± 6.73%, respectively. The need for less than 250 ml of plasma volume each sample made it possible to decrease sample preparation time. The method was successfully validated and proved appropriate for the analysis of atorvastatin in human plasma and can be applied for pharmacokinetics, bioavailability and bioequivalence studies.