Drought, an important environmental factor affecting the functioning of stream ecosystems, is likely to become more prevalent in the Mediterranean region as a consequence of climate change and enhanced water demand. Drought can have profound impacts on leaf litter decomposition, a key ecosystem process in headwater streams, but there is still limited information on its effects at the regional scale. We measured leaf litter decomposition across a gradient of aridity in the Ebro River basin. We deployed coarse- and fine-mesh bags with alder and oak leaves in 11 Mediterranean calcareous streams spanning a range of over 400 km, and determined changes in discharge, water quality, leaf-associated macroinvertebrates, leaf quality and decomposition rates. The study streams were subject to different degrees of drought, specific discharge (L s− 1 km− 2) ranging from 0.62 to 9.99. One of the streams dried out during the experiment, another one reached residual flow, whereas the rest registered uninterrupted flow but with different degrees of flow variability. Decomposition rates differed among sites, being lowest in the 2 most water-stressed sites, but showed no general correlation with specific discharge. Microbial decomposition rates were not correlated with final nutrient content of litter nor to fungal biomass. Total decomposition rate of alder was positively correlated to the density and biomass of shredders; that of oak was not. Shredder density in alder bags showed a positive relationship with specific discharge during the decomposition experiment. Overall, the results point to a complex pattern of litter decomposition at the regional scale, as drought affects decomposition directly by emersion of bags and indirectly by affecting the functional composition and density of detritivores.