Previous studies provide conflicting opinions on whether lower than average salinities in Gulf of Mexico (GOM) estuaries are likely to increase or decrease oyster harvests (Crassostrea virginica), which represented 69% and 54% of the United States oyster landings by weight, and dockside value, respectively, in 2003. The present study examined a 54-yr record (1950–2003) of oyster harvests and river discharge in five major estuaries in GOM states (Florida, Alabama, Mississippi, Louisiana, and Texas). Oyster landings were inversely related to freshwater inflow. Peaks in landings, 21 of 23 in West Florida, Alabama, Mississippi, and Texas combined, were coincidental with lows in river discharge from the major rivers in the estuaries. Lows in landings in these states (17 of 19) coincided with peaks in discharge of the major rivers feeding their estuaries. Landings in Breton Sound, Louisiana, were also inversely related to river discharge. The only exception to this pattern was for landings in the Plaquemines Parish, Louisiana, part of the Breton Sound estuary, where there were higher landings following increased Mississippi River discharge. The Bonnet Carré spillway, completed in 1931, diverts flood waters from the Mississippi River to Lake Pontchartrain, and it has been opened to reduce flood heights in 1937, 1950, 1973, 1975, 1979, 1983, and 1997. Twenty-five of 28 times after the spillway was opened, oyster landings in Mississippi were lower than in the other four states. The inverse relationship between freshwater inflow and oyster landings suggests that the proposed Bonnet Carré Freshwater Project, designed to reduce estuarine salinity, cannot be justified on the basis of anticipated higher oyster yields in Mississippi or Louisiana. Manipulating estuarine salinity in the GOM should be done within the context of the whole estuary and not just part of the estuary.