A simple, rapid and sensitive hollow-fiber with drop-to-drop solvent microextraction (HF-DDSME) combined with gas chromatography-mass spectrometry (GC-MS) has been successfully developed for extraction and determination of antidepressants drugs (AD) in blood sample. The parameters that affect the separation and preconcentration of AD from sample solution were investigated. Calibration curve obtained for three AD were in the range of 100-1,000; 150-1,200; and 80-1,200 ng mL -1 for amitriptyline, imipramine, and promethazine, respectively, with correlation coefficient (R 2 ) between 0.990 and 0.997. The limit of detection (LOD) obtained for amitriptyline, imipramine and promethazine was 25, 30 and 18 ng mL -1 , respectively. The developed method has been successfully applied for the determination of AD concentration in blood sample, and the recoveries for the spiked samples were in the range of 92.3-97.6%. The sample preparation procedure is very simple, effective and virtually solvent-free, and indicated to be a good alternative for the traditional liquid-liquid extraction. Finally, the proposed method was successfully applied for the determination of drug concentration of AD in human blood sample.