We conducted a study in the Sacramento-San Joaquin Delta to determine efficacy of the widely used herbicide fluridone in an estuarine ecosystem. The primary goal of SAV removal was restoration of open water habitat for endangered Hypomesus transpacificus (Delta Smelt). Over 18 months and multiple sets of multi-week fluridone applications, we monitored concentrations of fluridone and responses by SAV across pairs of treated and reference sites. Fluridone concentrations in the water were generally below the 2-5 parts per billion required for SAV control. Monitoring demonstrated these low water concentrations were likely due to dissipation by tides, despite use of pelleted fluridone formulations marketed for flowing water environments. Fluridone did, however, accumulate in sediment at concentrations hundreds of times higher than those measured in the water. Nonetheless, we did not observe lasting reductions in SAV abundance or changes in SAV community composition. By demonstrating lack of efficacy of one of the few herbicides permitted for use in this estuary, this study highlights the need for development of SAV management tools tailored to the challenges of hydrologically complex environments like estuaries.