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The content of a wide range of chemical elements has been studied in the Mzymta River waters using inductively coupled plasma spectrometry. The composition of the primary elements has been determined for different phases of the water regime. With respect to clarkes (the average concentrations of elements in continental river water), the waters of the river are enriched in 36 chemical elements during flood periods compared to 16 elements during low water periods. Conversely, the total concentrations of excess chemical elements are higher during low water periods as a result of the presence of Ca and Mg among these elements, the absolute concentrations are an order of magnitude higher than the concentrations of the primary macroelements during flood periods (Fe and Al). However, this feature does not influence the total mineralization of the waters, the average values of which are approximately the same for flood and low water periods: 72 and 79 mg/L, respectively. This is determined by a significant saturation of the river waters with rare earth elements, as well as Fe, Mn, Cs, Co, Al, Ga, P, Pb, Cd, As, V, Ti, Ge, Cr, Li, Ni, Sr, Zn, Ca, Ag, and Sn, during flood. The active entry of these elements into the river waters during this period is determined by abundant soil runoff and their capability for complexing and by adsorption of colloidal particles on the surface. The average content of trace elements in the waters of the Mzymta River is 2 times higher during flood than during low water period. The content of primary elements for flood decreases during low water period (when groundwater recharge contributes more to the formation of the river runoff). The maximum total saturation factors (total excess of element concentrations above background) of river waters for both phases of the water regime are observed in the middle reaches of the river, where zones of ore mineralization are clearly defined, and in the lower reaches, where the composition of the river water is significantly influenced by the natural–man-made factor. The latter is associated with the presence of road infrastructure and small human settlements in the river valley, where elemental inputs into the river are caused by soil dusting, excavation work, and the backfilling of construction sites with local rock formations, which are common in the basin but, at the same time, fragmented and therefore subject to more intense weathering and a higher rate of chemical element removal.