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Understanding factors influencing groundwater chemistry in regional groundwater basins is important to prevent groundwater pollution especially in arid areas where rainfall is low and water resources are limited. The present study assesses such factors in the regional, geologically diverse, groundwater basin of Wadi Umairy in Oman. The basin is composed of five different lithostratigraphic units with different hydraulic properties. Water samples (41) have been collected from the different units and analyzed for the major ions. Factor analysis and conventional hydrochemical methods were used to define the factors that have significant impact on the aquifer’s hydrochemistry. It was found that evaporation and mineral weathering/dissolution are the main factors defining the groundwater chemistry along the flow path from recharge to discharge zones, whereas anthropogenic activities and alkalinity are found to be of lesser effect, and the latter prevails when the rocks are predominantly monomineralic. It was concluded that in regional groundwater basins, recharge/discharge relations together with the flow scale control the hydrochemistry irrespective of lithological variation in the basin.