Abstract: A method coupling solid-phase extraction to high performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) was developed to simultaneously determining nine sweeteners (acesulfame, saccharin sodium, sodium cyclamate, sucralose, aspartame, alitame, neohesperidin dihydrochalcone, neotame, and stevioside) in refill liquids for e-cigarettes. The liquid samples were ultrasonically extracted by water, and the extracts were cleaned using SPE column equipped with C₁₈ packing material and concentrated by nitrogen blowing. The analytes were separated on Waters XBridge C₁₈ column using methanol-5 mmol/L ammonium acetate as the mobile phase for gradient elution, determined by tandem mass spectrometry in positive and negative ESI modes under multiple reaction monitoring (MRM), and quantified by using warfarin sodium as internal standard. The results showed that: 1) Under the optimal conditions, calibration curves were linear (R² > 0.998) for the nine sweeteners within their test concentration ranges. The limits of detection and quantification were 0.005-0.287 μg/mL and 0.017-0.956 μg/mL, respectively. The spiked recoveries of blank sample ranged from 82.96% to 114.01% with the relative standard deviations of 2.19%-5.18%. 2)The refill liquid samples for eight commercial e-cigarettes of different brands were tested by this method, only one sample was found containing neotame at 5.92 mg/kg. 3) This method was accurate, reliable and suitable for the simultaneous determination of nine sweeteners in refill e-liquids.