Modeling and simulation of a three-phase commercialscale reactor for the catalytic hydrotreating of vegetable oil is reported to analyze the effect of reactor characteristics and mode of operation on product yields and temperature profiles along the catalytic bed length and time-on-stream. The model considers the variation of superficial gas velocity and effects of diffusion inside the catalytic particle to generate information in a more realistic large-scale environment. A series of simulations performed at different operating conditions show that the reaction heat released and hydrogen consumption are higher than those found for petroleum distillate hydrotreating, which enhances a sudden decrease in product yields. This information is vital to propose reactor design strategies, i.e., cooling systems, for a sharp temperature increase to optimize the performance of the entire process.