In inductively-coupled plasma – mass spectrometry (ICP-MS) analyses, internal standards are often used to correct for signal variability. Determining the best internal standard has historically involved matching certain characteristics of the internal standard element like mass or first ionization energy to the analyte of interest. However, advances in ICP-MS such as reaction cell (RC) technology, which can effectively modify the ion beam or chemically alter the analyte of interest, introduce new considerations for the choice of internal standard. The commonly used internal standard elements 6Li, 45Sc, 69Ga, 74Ge, 89Y, 115In, 159Tb, 165Ho, 187Re, 193Ir, and 209Bi were analyzed under five different analytical conditions and displayed a wide range of RC behavior including suppressed signal, increased signal (collisional focusing) and product ion formation. The behavior of these elements is not correlated to first ionization energy or mass and the product ions formed with NH3 or O2 as a cell gas are not consistent for all elements. To evaluate their use as internal standards, several product ions were used to correct the mass-shifted analysis of As, Fe, S and Zn in the NIST standard reference materials SRM 1573a Tomato Leaves and SRM 1577c Bovine Liver. With few exceptions, both mass-shifted and on-mass internal standards were effective in correcting the analytes of interest. Poor performance of the internal standards could be explained by sample matrix specific interferences, highlighting the importance of understanding RC behavior and its influence on analyses.