One of the goals of the study is to establish the conditions that affect the water quality in the catchment area of the Mesta River (Southwest Bulgaria). This will help to distinguish the anthropogenic impact from natural factors, with geological setting in first place. For the formation of the chemical composition of the waters in regional aspect, the outcropped rocks are of major importance. In the considered area most widespread are mainly silicate rocks – about 75% of the total area. These are mainly different types of granites and to a much lesser extent granodiorites, quartz porphyries, quartz porphyrites (58%). Highly metamorphosed rocks such as gneisses, shales, amphibolites are also important – 26%, as well as volcanic (rhyodacites, dacites, ignimbrites and their tuffs) – 5%. These rocks occupy the relatively higher and steeper parts of the catchment area and fractured rocks aquifers are formed in their weathering zones. Given the low solubility of the minerals forming these rocks and their rapid runoff, the waters in them show low TDS content. Due to the processes of chemical weathering, they provide some of the main macrocomponents, determining the chemical type of groundwaters – Na, Ca, Mg, HCO3. Although with a relatively small area (about 5%), the marbles, which are significantly karstified are characterized by the formation of large amounts of water. Active karst processes are the cause for the predomination of hydrogencarbonate-calcium type of waters. Neozoic sandstones, conglomerates and clays (about 8% of the total area) are deposited in lower parts of the river valley, in the range of tectonic grabens. They form a layered aquifer complex, where due to the slower movement of water and longer water-rock contact, groundwater has a relatively higher TDS content. Along with the regional hydrogeological and hydrochemical features, the geological setting is the reason for the probable presence of local hydrochemical anomalies. They are often associated with fractures and pegmatite veins, in which ore manifestations and indications of Pb, Zn, Cu, Fe, W, Mo, Ag, Au, Bi, Sb, as well as talc, asbestos and muscovite have been found. Elevated contents of Fe, Mn and U are found in some places too. The localization of such zones (over 100 in total) will help to correctly clarify the genesis of undesirable deviations in groundwater quality. Thermal water deposits, some of which have conditions for mixing with cold groundwater, are also examined.