Two-phase flows across tube bundles are very commonly found in industrial heat exchange equipment such as shell and tube heat exchangers. However, recent studies published in the literature are generally performed on devices where the flow crosses the tube bundle in only a vertical or horizontal direction, lacking geometrical fidelity with industrial models, and the majority of them use air and water as the working fluids. Also, currently, experimental approaches and simulations are based on very simplified models. This paper reports the simulation of a laboratory full-scale tube bundle with a combination of vertical and horizontal flows and with two different baffle configurations. Also, it presents a similarity analysis to evaluate the influence of changing the fluids to hydrogen and diesel in the operational conditions of the hydrotreating. The volume of fluid (VOF) approach is used as the interface phenomena are very important. The air/water simulations show good agreement with classical correlations and are able to show the stratified behavior of the flow in the horizontal regions and the intermittent flow in the vertical regions. Also, the two baffle configurations are compared in terms of volume fraction and streamlines. When dealing with hydrogen/diesel flow using correlations and maps made for air/water, superficial velocity is recommended as similarity variable when a better prediction of the pressure drop is needed, and the modified superficial velocity is recommended for prediction of the volume-average void fraction and the outlet superficial void fraction.