This work focused on determining iron, TiO2, and pH interaction in the photocatalytic oxidation of the pesticide imidacloprid with TiO2/SiO2 catalysts at pilot-plant scale when TiO2/SiO2, iron and H2O2 are combined. Experimental design techniques have been applied to achieve this goal. The response variable in the mathematical model that best fits the results is the initial reaction rate logarithm as a function of the linear effect of the three variables, the interaction between iron dose and pH, and the quadratic effect of pH and titanium dioxide concentration. The analysis of the results shows that the pH is the most influential variable, followed by the initially added dose of iron, and finally TiO2 concentration. The degradation reaction rates observed are the result of the simultaneous combination of a large number of homogeneous and heterogeneous catalytic reactions related to TiO2 and homogeneous photo-Fenton photocatalytic mechanisms. At acid pH, the influence of the semiconductor-based pathway is quantitatively lower than that of degradation by photo-Fenton. However, above a critical pH, a synergistic effect between iron and TiO2 degradation mechanisms is observed, increasing the overall reaction rate.