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Field and laboratory studies have shown that mayflies (Ephemeroptera) tend to be relatively sensitive to elevated major ion concentrations, but little is known about how ionic composition influences these responses. The present study evaluated the acute toxicity of major ion salts to the mayfly Neocloeon triangulifer over a range of background water quality conditions. The mayfly was particularly sensitive to Na2SO4, with the median lethal concentration (LC50) of 1338 mg SO4/L being lower than LC50s reported for 7 other species at that hardness. Increasing hardness of the dilution water from 30 to 150 mg/L (as CaCO3) resulted in doubling of LC50s for sodium salts, and an approximately 1.5-fold increase in LC50 for MgSO4. Potassium salt toxicity was not strongly influenced by hardness, consistent with findings for other species. When hardness was held constant but the Ca to Mg ratio was manipulated, the ameliorative effect on Na2SO4 and NaCl did not appear as strong as when hardness was varied; but for MgSO4 the amelioration relative to Ca activity was similar between the 2 experiments. The toxicity of K salts to N. triangulifer was similar to Na salts on a millimolar basis, which contrasts with several other species for which K salts have been much more toxic. In addition, the toxicity of KCl to N. triangulifer was not notably affected by Na concentration, as has been shown for Ceriodaphnia dubia. Finally, plotting LC50s in terms of ion activity (Cl, SO4, Na, Mg, or K) over the range of Ca activities in dilution water resulted in significant positive relationships, with comparable slopes to those previously observed for C. dubia over the same range of Ca activities. (C) 2018 SETAC