The effect of the different antifoulant agents on the performance of a NiMoP/Al2O3 catalyst for hydrotreating of residuum was evaluated in an industrial scale reactor. Two kinds of antifoulant, e.g., P-containing and P-free, were added to the feedstock of the crude oil to prevent scaling in the heat exchanger of a single-stage once-through (SSOT) hydrotreating processor. The results show that addition of P-containing antifoulant to the feedstock lowers the catalyst activity for hydrodesulfurization (HDS) and accelerates the deactivation of the catalyst, while P-free antifoulant has little influence on the catalyst performance. During the reaction some heteroatoms from the oil, such as iron sulfide and nickel sulfate, were deposited on the catalysts, but they appeared to have little effect on the activity. The main factor influencing the activity of catalyst was P-containing antifoulant, which deposited on the outer layer of the trilobe catalyst pellets. During the reaction, the deposited P-containing compounds formed a condensed layer, deactivating the most accessible active sites at the outer layer of the pellets and depressing diffusion to the inner layer, which is still active. In addition, it appeared that P-containing compounds caused the active catalyst component, i.e., MoS2 aggregate, resulting in the deactivation of the catalyst. In the case of the P-free antifoulant system, deactivation of the catalyst probably resulted from coking and adsorbed nitrogen compounds. Therefore, the addition of P-containing antifoulant to oil feedstocks. results, in faster catalyst deactivation and is not recommended for industrial oil refining.