Single particle inductively coupled plasma time-offlight mass spectrometry (spICP-TOFMS) is a powerful analytical technique for quantifying elements in nanoparticles and microparticles; however, like most ICP-MS-based measurements, matrix effects can be a major challenge for accurate quantification in spICP-MS. Here, we report the use of online microdroplet calibration to overcome extreme matrix effects observed for the analysis of nanoparticles and microparticles in seawater. With online microdroplet calibration, particle-containing samples are introduced into the ICP along with monodisperse microdroplets containing known element mass amounts. The microdroplet standards, which experience the same plasma conditions as the analyte particles, are used to measure matrix-matched absolute element sensitivities. With online microdroplet calibration, one multielemental standard can be used to determine the element mass amounts in diverse types of analyte particles independent of the sample matrix. We evaluate the matrix tolerance of spICP-TOFMS with online microdroplet calibration through the analysis of metal nanoparticles, polystyrene microplastic beads doped with rare-earth elements, and metaloxide submicrometer particles in artificial seawater. Our results demonstrate mass recoveries of 98−90% for the analysis of individual gold NPs in ultrapure water to 99% seawater. In the analysis of food-grade TiO 2 submicron particles, accurate Ti-mass per particle is determined with matrix-caused signal attenuation up to 80% in a pure seawater matrix. We also demonstrate accurate diameter determinations of individual 3.4 μm polystyrene beads at concentrations of up to 80% simulated seawater. Furthermore, simultaneous and accurate quantification of rare-earth elements in the polystyrene beads is achieved.