A sensitive and selective analytical method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) has been developed for the simultaneous determination of rimonabant and orlistat in weight-loss functional foods. After the foods were extracted under accelerated solvent extraction, the HPLC separation was performed on a Waters Atlantis T3 column (150 mm x 2.1 mm, 3 microm) with a linear gradient elution program of methanol and 10 mmol/L ammonium acetate as the mobile phase. Electrospray ionization was applied and operated in the positive ion mode. The results showed that the limits of detection for the rimonabant and orlistat were 0.5 mg/kg. The calibration curves showed good linearities for rimonabant and orlistat in the range of 0.5 - 100 microg/L, and the correlative coefficients were 0.998 9 and 0.999 4, respectively. The mean recoveries at the 3 spiked levels (2, 5, 10 mg/kg) were 80.5% - 102.1% with the intra-day precision less than 6% and the inter-day precision less than 8%. The work studied the mass spectrum characterization of the 2 drugs and speculated on the fragmentation pathways. The method is sensitive, reproducible and adapts to the determination of rimonabant and orlistat in different weight-loss functional foods.