In this work, a novel method was developed for the determination of the volatile elements Cd, Pb, and Zn in high purity tantalum pentaoxide (Ta2O5) by in situ matrix removal and electrothermal vaporization inductively coupled plasma mass spectrometry (ETV-ICP-MS). A polytetrafluoroethylene slurry (PTFE) was used as a chemical modifier in ETV for converting both the matrix (Ta) and the volatile elements into their fluorides. This strategy greatly enhanced the difference in the volatility between the analytes and the matrix. As a result, the Ta matrix was removed in situ as a more volatile TaF5 without signal loss of the analytes due to the formation of their fluorides with good thermal stability. Under the optimum operating conditions, the detection limits (DLs) for Cd, Pb, and Zn were 1.4, 3.2, and 6.8 ng g(-1) with relative standard deviations (RSDs) less than 6.0%, respectively. This method was applied to the determination of the trace volatile elements Cd, Pb, and Zn in high purity Ta2O5, and the results were in good agreement with those obtained by conventional pneumatic nebulization (PN) ICP-MS after the separation of the matrix with a solvent extraction procedure.