Core-shell silica particles have been developed and employed by various manufacturers for fast and efficient HPLC separations with relatively low back pressure. However, core-shell silica particles are usually fabricated by the time-consuming layer-by-layer technique and usually followed by a lengthy classification process to obtain uniform particles. Recently, we have developed a onepot synthesis method at room temperature to produce the unique sphereson-sphere (SOS) silica particles. These SOS particles are comprised of silica nanospheres attached to silica microspheres. The size and number of silica nanospheres are tunable. The interstices between the surface silica nanospheres on the solid microspheres generate the macroporosity for fast and efficient HPLC separations with low back pressure, particularly for large bio-macromolecules. Importantly, these SOS particles are very uniform directly from synthesis (hence classification in unnecessary) and mesoporosity and additional functional particles may be introduced so that these particles can be efficiently used for fast separation of a wide range of analytes, including peptides, proteins, small molecules, and isomers. This talk will cover the preparation and characterization of SOS particles and their various applications in HPLC.