Recognition of the global loss of subtidal oyster reefs has led to a rise in reef restoration efforts, including in the Gulf of Mexico. Created reef success depends entirely on selecting a location that supports long-term oyster growth and survival, including the recruitment and survival of on-reef oysters. Significant changes in estuarine salinity through management of freshwater inflows and through changed precipitation patterns may significantly impact the locations of optimal oyster restoration sites. These rapid shifts in conditions necessitate a need to better understand both impacts to on-reef oyster growth and population development, and variation in oyster stock performance. Oyster growth, mortality, condition, and disease prevalence were examined in three different stocks of oysters located in protected cages, as well as oyster recruitment and mortality on experimental reef units in three different locations representing a salinity gradient, along the Louisiana Gulf coast in 2011 and 2012. Over a 2-y period, the high-salinity site had highest oyster growth rate in protected cages but demonstrated the least likelihood for reef development based on on-reef oyster population failure, likely because of predation-related mortality (high recruitment and 100% mortality). In contrast, the midsalinity site with moderate oyster growth and on-reef recruitment and low mortality demonstrated a higher likelihood for reef development. The lowest salinity site exhibited extreme variability in all oyster responses between years because of extreme variation in environmental conditions during the study, indicating a low likelihood of long-term reef development. Whereas limited differences in stock performance between sites were found, the range of site environmental conditions tested was ultimately much lower than expected and may not have provided a wide enough range of conditions. In areas with limited, low recruitment, or rapidly changing environmental conditions, seeding with stocks selected for best growth and survival under expected future environmental conditions could better ensure reef development by using oyster populations best suited to the predicted conditions. With rapidly changing estuarine conditions from anthropogenic activities and climate change, siting of oyster reef restoration incorporating both oyster population dynamics and in situ biotic and abiotic interactions is critical in better directing site selection for reef restoration efforts.