Sputtered neutral mass spectrometry (SNMS), which decouples ionization from sputtering, has greatly reduced the effect of the sample matrix. Its application to the quantification of powders has, however, resulted in many other uncertainties. An investigation of artifacts associated with the quantification of powders was carried out using W and Cr powders and several binder systems including Ag, Au, and C. The signal intensity detected in SNMS was significantly affected by the powder’s particle size and its preparation for analysis. The binder used in forming a pellet caused spectral interference and coating artifacts. Pressing powders onto In foil eliminated these problems, but did not result in a consistent foil coverage. Regardless of the preparation method, the particle size of powders had a strong influence on the intensity of the detected signal. The surface area of the powders can be used to project the intensity of the signal measured.