In X-ray Fluorescent Spectrometric (XRF) analysis, particle size effect and the matrix effect were reported when the powder tableting method was used. However, under certain particle size, tableting time and pressure, the effects existed only for light metals such as Na and Ca rather than heavy metal such as Mo, Cu and Pb. Based on these findings, an optimized powder tableting sample preparation method for reducing particle size effect and other interferences was established for simultaneous determination of Mo, W, Cu, Pb, Zn, F, S, As and Bi in molybdenum ore samples by XRF. Low pressure polyethylene powder was used as the liner material to reduce cost; the sample powder was tabletted under 30 t pressures for 30 s. The prepared pellet was smooth with low moisture adsorption and could be stored for long periods without shape change. Particle size effect and matrix effect were diminished after calibration with national sulfide ore reference materials. An empirical coefficient was applied to reduce the influence of spectrum overlap and matrix interferences. The method precision (RSD) was < 2.1%, and the results were consistent with those obtained by other analytical methods. Compared with the fusion sample preparation method, the optimized powder tableting method demonstrates a lower detection limit. The detection limit for Mo was 3.67 μg/g vs. 450 or 24 μg/g by the fusion method, and 1.13 μg/g for As vs. 7.8 μg/g by the normal powder tableting method.