In this study, the nitration of o-nitrotoluene (NT) with mixed acid as a model fast liquid-liquid multiphase reaction was conducted in the packed and nonpacked microchannel reactors. Better reaction performance could be obtained in the packed microchannel reactor compared with the nonpacked microchannel reactor because of its excellent mass transfer performance. The conversion of NT reached 94% in the packed microchannel reactor even when the reaction time was less than 3 s. A parameter, which represented the coupling of mass transfer and residence time in microdevices, was proposed for explaining and anticipating nitration process in microchannel reactors. In addition, the effects of some operating parameters on reaction performance, such as the composition of mixed acid and reaction temperature, were also investigated experimentally. (C) 2010 American Institute of Chemical Engineers AIChE J, 57: 1409-1418, 2011