Samples containing a nickel phosphide precursor were synthesized by the impregnation method using TiO2-pillared sepiolite (Ti-Sep) as a support, nickel hydroxide as a nickel source, and phosphorous acid as a phosphorus source. From these precursor samples, Ni2P/Ti-Sep catalysts with Ni content ranging from 5%-25% (w, mass fraction) were prepared by temperature-programmed reduction. Thiophene hydrodesulfurization (HDS) was used to investigate the HDS activity of the catalysts. The catalysts were characterized by X-ray powder diffraction (XRD), N-2 adsorption-desorption, thermal gravity analysis (TGA), transmission electron microscope (TEM), and Fourier transform infrared spectroscopy (FTIR). The results demonstrated that the specific surface area and pore volume of Ti-Sep were enlarged and catalyst thermal stability was improved. In addition, the layer spacing of sepiolite was also increased. As a consequence, the active component, Ni2P, can be well dispersed on the interlayer and outer surface of Ti-Sep. Moreover, the layered sepiolite structure remained intact in the Ni2P/Ti-Sep catalysts. Consequently, thiophene conversion on Ni2P/Ti-Sep is improved compared with Ni2P/Na-Sep (NaCl-modified sepiolite) and Ni2P/HCl-Sep (HCl-modified sepiolite), which were prepared on sepiolite without Ti-pillaring. Ni2P/Ti-Sep with a Ni loading of 15% (w) shows the highest activity among all of the studied catalysts, on which the conversion of thiophene can reach 100% at 400 degrees C.