Separating target particles or cells from a heterogeneous mixture is often critical to many chemical and biomedical applications. Pinched flow fractionation (PFF) is a microfluidic technique that utilizes the laminar flow profile to continuously separate particles by size. We demonstrate that the flow-induced inertial lift force in microchannels can be exploited to significantly increase the particle displacement in PFF due to its strong size dependence. This inertia-enhanced PFF (iPFF) technique can offer at least one-order-of-magnitude higher particle throughput than PFF does at the same sheath flow rate. Moreover, it is able to work effectively in a large range of Reynolds number that spans more than 1 order of magnitude in the current study. In addition, iPFF is found to work most effectively in a rectangular microchannel with a width-to-height aspect ratio of around 2.