Abstract: A method for simultaneous determination of 7 phenolic compounds (phenol, o-cresol, m-cresol, p-cresol, catechol, resorcinol, hydroquinone) in mainstream cigarette smoke was developed using gas chromatography-tandem mass spectrometry (GC-MS/MS). The total particulate matter (TPM) of 5 cigarettes in mainstream cigarette was trapped by a 44 mm Cambridge filter pad with a Cerulean SM450 smoking machine under standard smoking condition. The filter pad which collected TPM was extracted on an ultrasonic generator for 20 min with 50 mL isopropanol and 100 μL ISTD solution containing 1 mg/L of 1-phenylethyl propionate. The solution extract was filtered through 0.45 μm pore size nylon filters, and then was analyzed by GC-MS/MS under multiple reaction monitoring (MRM) mode and was determined by ISTD method under the optimized conditions. In order to get good extraction efficiencies of phenolic compounds during a short time, 4 different extraction solvents (cyclohexane, dichloromethane, isopropanol, methanol) , 3 different extraction solvent volumes (20, 50, 100 mL) and 6 different ultrasonic extraction times (5, 10, 20, 30, 40, 60 min) were tested. The optimum condition was that 50 mL isopropanol extracted for 20 min. 4 compounds (propyl benzoate, 1-phenylethyl propionate, n-heptadecane, benzyl benzoate) were tested for choosing the suitable ISTD compounds. The results indicate that propyl benzoate and 1-phenylethyl propionate are suitable for ISTD compounds. 3 different polarity capillary columns (HP-5MS UI, DB-35MS, HP-INNOWAX) with the same column dimensions (30 m×0.25 mm×0.25 μm) were inspected. Both the best separation and peak shapes of seven phenolic compounds are achieved on the HP-5MS UI capillary column. The results showed that the linearity of phenols were above 0.998 6. The limits of quantification (LOQs) were 0.012-0.021 μg/cig. The recoveries were 91.1%-107.7% with the relative standard deviations (RSDs) lower than 6.6%. It was clearly advantageous for assays of phenolic compounds present in complicated matrices of mainstream cigarette smoke. As a part of the validation procedure, 12 brands of cigarettes were tested by the designed method. This method is suitable for the rapid determination of seven phenolic compounds in mainstream cigarette smoke with easy operation, high sensitivity, excellent precision and high throughput.