The Volta Basin in West Africa is a region sensitive to water shortage. Future climate conditions therefore may put additional stress on the competition for the scarce water resources between industry, agriculture, and households. For an investigation of the sensitivity of the hydrological regime to global climate change in the data-sparse and poorly gauged region of the Volta Basin, joint regional climate–hydrology simulations were performed. MM5 was used as a regional climate model to downscale two time slices of a global ECHAM4 simulation to a resolution of 9 km. These regional climate simulations were used to drive a physically based, distributed hydrological model at 1 km resolution. The performance of the model components and the joint model system was evaluated for different historical periods. Results show that discharge in the Volta Basin reacts highly sensitively to precipitation differences. The pronounced rainfall decrease at the beginning of the rainy season is not transferred to discharge changes. During the rainy season most of the surplus rainfall evaporates due to a strong increase in evaporation as a consequence of higher near-surface air temperatures. The average change signal in precipitation, as well as surface and subsurface hydrology variables, lies in most variables within the range of inter-annual variability, but regionally stronger signals are also observed.