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This study aimed to investigate the effect of titanium dioxide (TiO2) nano additives on the thermal performance of a pilot-scale cross-flow cooling tower. Moreover, it is a continuation of our previous study on the effect of using multi-walled carbon nanotubes (MWCNTs) nanofluid, and the results were compared with the results of TiO2 and previous work. An experimental design by response surface methodology (RSM) based on central composite design (CCD) with two factors (concentration and flow rate) was used to study the effectiveness of the setup, Merkel number, and the cooling range. The nanofluids were prepared by the two-step method. The stability tests were performed considering different surfactants such as Gum Arabic, Triton X-100, and sodium dodecyl sulfate, and Gum Arabic was determined as the optimal surfactant. The visual method, dynamic light scattering (DLS), and Zeta potential analyses were used to ensure the stability of the nanofluids and determine the size distribution of the nanoparticles in the nanofluids. The findings revealed that the heat transfer characteristics of the working fluid were improved with the addition of nanoparticles. Moreover, by comparing the effect of nanoparticles, it was found that MWCNTs could enhance the thermal features better than TiO2. The nanofluid containing 0.085 wt% of the MWCNTs improves the Merkel number, effectiveness, and cooling range by 28, 10.2, and 15.8%, respectively, whereas these values for TiO2 containing nanofluids are 5, 4.1, and 7.4%, respectively. MWCNTs nanofluid with a concentration of 0.069 wt% and a flow rate of 2.092 kg/min was proposed for optimal system setup. Under these conditions, the cooling range, effectiveness, and Merkel number were about 23.5, 55.75%, and 0.64, respectively. [ABSTRACT FROM AUTHOR]