Understanding the processes controlling the physics, chemistry, and biology of the San Francisco Estuary and their relation to climate variability is complicated by the combined influence on freshwater inflows of natural variability and upstream management. To distinguish these influences, alterations of estuarine inflow due to major reservoirs and freshwater pumping in the watershed were inferred from available data. Effects on salinity were estimated by using reconstructed estuarine inflows corresponding to differing levels of impairment to drive a numerical salinity model. Both natural and management inflow and salinity signals show strong interannual variability. Management effects raise salinities during the wet season, with maximum influence in spring. While year-to-year variations in all signals are very large, natural interannual variability can greatly exceed the range of management effects on salinity in the estuary.