Most of the global population lives in lowlands, where water demand is highest. Therefore, understanding the dependence of lowland regions on mountain water at a global scale is crucial as mountains provide an essential contribution to lowland water resources. Yet, interannual variability remains poorly studied in this context, although it is a key factor influencing water supply and demand. In this study, we used global simulations to contrast lowland and mountain runoff and future changes across all river basins larger than 10,000 km2 globally, focusing on seasonality and interannual variability. We also examined the contribution of mountain runoff to lowland water use, its seasonality and interannual variability and its potential future changes. Our results indicate that relative interannual runoff variability is lower in mountain regions compared to lowlands in 70% of river basins. Lowland water use exhibits considerable interannual variability with greater reliance on mountain runoff during years with low lowland runoff. By the end of the century, under the SSP5-8.5 pathway, the absolute volume of lowland water abstraction reliant on mountain runoff is projected to increase in most river basins compared to the past due to socio-economic changes. Yet, its share relative to total lowland surface water abstraction is projected to decline in many basins due to increased average lowland precipitation. Possible implications of such an increased reliance on mountain runoff include heightened water conflicts, as growing dependence on upstream mountain runoff may intensify transboundary challenges.