Based on previous observations that hardness (and potentially chloride) influences sodium sulfate toxicity, the objective of the current study was to quantify the influence of both chloride and water hardness on acute toxicity to Hyalella azteca and Ceriodaphnia dubia. In addition, observed toxicity data from the present study were compared to toxicity predictions by the salinity/toxicity relationship (STR) model. Hardness had a strong influence on sulfate toxicity that was similar for both crustaceans, and nearly identical median lethal concentration (LC50)/hardness slopes were observed for the two species over the tested range. Chloride had a strong but variable influence on sulfate acute toxicity, depending on the species tested and the concentration range. At lower chloride concentrations, LC50s for H. azteca strongly were correlated positively with chloride concentration, although chloride did not affect the toxicity of sodium sulfate to C. dubia. The opposite trend was observed over the higher range of chloride concentrations where there was a negative correlation between chloride concentration and sulfate LC50 for both species. The widely ranging values for both species and a high correlation between LC50s in terms of sulfate and conductivity suggested that, whether based on sulfate, conductivity, or total dissolved solids (TDS), attempts at water quality standard development should incorporate the fact that water quality parameters such as hardness and chloride strongly influence the toxicity of high TDS solutions. The STR model predicted toxicity to C. dubia relatively well when chloride was variable and hardness fixed at approximately 100 mg/L; however, the model did not account for the protective effect of hardness on major ion/TDS toxicity.