Abstract Laser ablation inductively coupled plasma mass spectrometry (LA-ICP/MS) has been successfully deployed by researchers at the Pacific Northwest Laboratory for the analysis of Hanford nuclear waste. This effort required research to determine the relative importance of the numerous parameters involved in LA-ICP/MS. These factors include laser parameters and sample matrix variables. The precision in relative concentrations was determined as a function of laser wavelength. Ablation at 355 or 266 nm gave precision of 5–10%, while the value for 532 nm was 25% and for 1064 nm was 40%. Analysis of the data for relative fractionation between elements showed large differences in the IR for volatile vs. refractory elements. The UV ablation gave results that were much less dependent on matrix effects and showed minimal or no fractionation. Measurements of the particle distribution produced by laser ablation prior to transfer to the ICP/MS were made as a function of laser wavelength and pulse energy. These results show that the laser wavelength and pulse energies that provide the best precision and accuracy for analysis of glass or tank waste simulant materials produce particle size distributions with the majority of ablated material present as particles from 0.1–1.0 μm in diameter. This size range is important for quantitative transport to the ICP/MS and for complete digestion of the particles in the plasma. The particle counts were used to normalize the mass spectra of glasses having widely different opacities and laser ablation efficiencies resulting in quantitative analysis of these samples.