The transboundary Mekong River is facing two ongoing changes that are expected to significantly impact its hydrology and the characteristics of its exceptional flood pulse. The rapid economic development of the riparian countries has led to massive plans for hydropower construction, and projected climate change is expected to alter the monsoon patterns and increase temperature in the basin. The aim of this study is to assess the cumulative impact of these factors on the hydrology of the Mekong within next 20-30 yr. We downscaled the output of five general circulation models (GCMs) that were found to perform well in the Mekong region. For the simulation of reservoir operation, we used an optimisation approach to estimate the operation of multiple reservoirs, including both existing and planned hydropower reservoirs. For the hydrological assessment, we used a distributed hydrological model, VMod, with a grid resolution of 5 km × 5 km. In terms of climate change's impact on hydrology, we found a high variation in the discharge results depending on which of the GCMs is used as input. The simulated change in discharge at Kratie (Cambodia) between the baseline (1982-1992) and projected time period (2032-2042) ranges from −11% to +15% for the wet season and −10% to +13% for the dry season. Our analysis also shows that the changes in discharge due to planned reservoir operations are clearly larger than those simulated due to climate change: 25-160% higher dry season flows and 5-24% lower flood peaks in Kratie. The projected cumulative impacts follow rather closely the reservoir operation impacts, with an envelope around them induced by the different GCMs. Our results thus indicate that within the coming 20-30 yr, the operation of planned hydropower reservoirs is likely to have a larger impact on the Mekong hydrograph than the impacts of climate change, particularly during the dry season. On the other hand, climate change will increase the uncertainty of the estimated reservoir operation impacts: our results indicate that even the direction of the flow-related changes induced by climate change is partly unclear. Consequently, both dam planners and dam operators should pay closer attention to the cumulative impacts of climate change and reservoir operation on aquatic ecosystems, including the multibillion-dollar Mekong fisheries. © Author(s) 2012.