Immunomodulatory drugs lenalidomide (LENA) and pomalidomide (POMA) are synthetic compounds derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. LENA is used as a treatment for myeloma and blood disorders called myelodysplastic syndromes. The maximum clinical dose of LENA for some haematological cancers is generally <= 25 mg. Therapeutic drug monitoring (TDM) is important for the individualization of drug dosage. A highly sensitive and high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) assay was developed and validated for the quantification of LENA in human plasma. LENA was extracted from human plasma by liquid-liquid extraction by ethyl acetate and analysed using a reversed phase isocratic elution on a Poroshell 120 EC-C18, (4.6 - 50 mm, 2.7 mu m) column. 0.1% formic acid: methanol (10:90% v/v), was used as mobile phase and detection was performed by triple quadrupole mass spectrometry LC-MS/MS using jet stream electrospray ionization in negative mode. POMA was used as the internal standard (IS). Analyte and IS were detected by tandem mass spectrometry using multiple reaction monitoring (MRM) of precursor-product ion transitions with 0.100 s dwell time, at m/z 258.0 > 213.0 for LENA and m/z 272.0 > 161.0 for POMA. The calibration curves were consistently accurate and precise over the concentration range of 20 ng/mL to 1000 ng/mL in plasma for LENA. This novel LC-MS/MS method competes with all the regulatory requirements and shows satisfactory accuracy and precision. It is sufficiently sensitive for the performance of pharmacokinetic, bioequivalence and TDM studies in humans.