The isotopic analysis of particles containing sub-pg to pg levels of uranium, released from nuclear material handling, has been proven as an efficient tool for international safeguard purposes. Precise and accurate measurement of both enrichment and the minor isotopes is, however, a challenging analytical task due to the low levels of material. One of the mainstay techniques for particle measurement is Secondary Ion Mass Spectrometry (SIMS), this study evaluates the analytical benefit of an alternative in the form of large geometry SIMS (LG-SIMS), which combines high transmission with high mass resolution. We report here that LG-SIMS instruments provide a significantly better measurement quality than the small geometry SIMS as almost all isobaric background interferences are removed at a high useful ion yield. Useful yield measurements, performed on uranium oxide particles with calibrated uranium content, showed an overall useful yield of 1.2% for the LG-SIMS at a mass resolution of 3000. These improvements were then demonstrated by comparing results from actual nuclear inspection samples measured on both instruments. Additional benefits include an increased ability to detect particles of interest in a dust matrix while simultaneously reducing the time of sample analysis. An evaluation on the performance of LG-SIMS compared to Thermal Ion Mass Spectrometry (TIMS) is also presented. This evaluation shows that LG-SIMS has an advantage due to its high ion yield but with a limitation in the detection limit of 236U at higher enrichments due to the necessity for a hydrogen correction.