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A sensitive method for simultaneous analysis of nine fourth-generation antidepressants in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) is presented. The method was used with a Waters Acquity UPLC LC system, an Acquity TQD MS-MS system, and a Poroshell 120 EC-C18 separation column. For extraction of the target compounds, solid-phase extraction with Oasis HLB cartridges was used. All compounds were detected with retention times lower than 3 min. The calibration curves for the antidepressants spiked into human plasma showed similar good linearities in the range of subnanogram to nanogram per milliliter. The detection limits (signal-to-noise ratio = 3) were in the range of 0.2-100 pg/ml. The method gave satisfactory recovery rates, accuracy, and precision for quality control samples spiked with these drugs. To further validate the present method, 25 mg of milnacipran was orally administered to a healthy male volunteer, and the drug concentrations in plasma were measured in samples collected 0.5, 1, 2, 4, and 8 h after dosing. The concentrations were in the range of 31.2-56.8 ng/ml. To our knowledge, this is the most sensitive quantitative method for fourth-generation antidepressants so far reported, and should prove very useful in forensic and clinical toxicology. In addition, the quantitative analysis of tianeptine by LC-MS-MS is first described in this study.