The objective of this paper is to present the advantages and problems related to the application of a multi-layer model in hydrogeological investigations, exemplified by the Main Groundwater Basin No. 338. The main aquifer in this basin is Neogene, but Quaternary, Cretaceous and Palaeozoic-Proterozic aquifers have also been identified there. Due to the presence of numerous permeable layers, separated by impermeable ones of irregular distribution in the Neogene aquifer, 27 model layers have been distinguished, including 10 water-bearing horizons. A large number of model blocks caused the increase of the computational time, and a large number of layers have lengthened the calibration time of the model. However, anthropogenic or geologic threats to multi-layer structures have justified such a large number of layers, enabling the water balance for the selected part of the basin orfor the selected depth intervals with groundwater of good or bad status.