The average length of time land-borne compounds remain within an aquatic system is one of the key parameters controlling its biochemical processes. This study explores the magnitude and sources of daily, seasonal, and interannual variability of river water residence time in the Sau Reservoir, a prototypical example of a Mediterranean water supply. Daily estimates of residence time from 1998 to 2005 were obtained from a series of tracer experiments simulated with a one-dimensional physical model, based on actual observations and synthetic scenarios. Results highlight that multiple in situ factors, both natural and managed by humans, affect the residence time in reservoirs. Simulated residence times varied on average ∼30% on a daily basis, as a result of natural meteorological (17%) and river inflow temperature (11%) variability. The management of withdrawal depths largely controlled the seasonal variations: The practice of withdrawing water from the shallowest outlet, which was close to the intrusion level of summer inflows, promoted shorter residence times in summers than winters. Interannual variability was primarily associated with the natural variability of inflow volume (25%), and secondarily with surface meteorology (8%). Excessive withdrawals prior to and during long dry periods, however, drastically reduced the reservoir storage capacity and withdrawal options, leading to shorter residence times in dry years. The flushing time, calculated as the ratio of storage volume and flow rates, captured the trends in annual mean residence times reasonably well but not daily and seasonal residence times.