3D reactive transport model is an efficient tool to simulate ISR operation: indeed the whole process is based on reacting fluid circulation in porous media. The simulation can help quantify the processes at stake, and optimize the ore dissolution rate and the use of reagents. It can also be used to test the efficiency of alternative well patterns or to refine well screens vertical position within the ore body. The model relies on an appropriate description of uranium bearing aquifer. 3D geologic block models based on geological observations and geostatistical reconstruction were used. They describe the spatial distribution of both hydrodynamic and geochemical units (including uranium and other mineral concentrations). Also, a correct assessment of the chemical reactions (thermodynamic and kinetics) at stake is necessary. This study details the application of a 3D reactive transport approach (using the code HYTEC) at operation scale in Kazakhstan (technological blocks, approx. 70 wells each). Among other simulation results available, it has been shown that the evolution of the uranium concentration in the production wells and the acid consumption can be accurately forecasted. Moreover, various scenarios of operational optimization, mainly dedicated to well patterns and wells screen localization refinement, were simulated. The results assess the interest of using 3D reactive transport modelling tool for such optimization purposes.