It has long been known that the toxicity of the lampricide 3-trifluoromethyl-4-nitrophenol (TFM) is influenced by chemical and physical properties of water. As the pH, conductivity, and alkalinity of water increase, greater concentrations of TFM are required to kill sea lamprey (Petromyzon marinus) larvae. Consequently, the concentration of TFM required for effective treatment varies among streams. Brown trout (Salmo trutta) and sea lamprey larvae were exposed to a series of TFM concentrations in a continuous-flow diluter for 12 h. Twenty five exposures were conducted at various water alkalinities and pHs that treatment personnel encounter during lampricide treatments. Survival/mortality data were analyzed for lampricide concentrations that produced 50 and 99.9% mortality (LC₅₀ and LC_99.9) for sea lamprey larvae and 25 and 50% mortality (LC₂₅ and LC₅₀) for brown trout. Linear regression analyses were performed for each set of tests for each selected alkalinity by comparing the 12-h post exposure LC_99.9 sea lamprey data and LC₂₅ brown trout data at each pH. Mortality data from on-site toxicity tests conducted by lampricide control personnel were compared to predicted values from the pH/alkalinity prediction model. Of the 31 tests examined, 27 resulted in the LC₁₀₀s (lowest TFM concentration where 100% mortality of sea lamprey was observed after 12 h of exposure) falling within 0.2 mg/L of the predicted sea lamprey minimum lethal (LC_99.9) range. The pH/alkalinity prediction model provides managers with an operational tool that reduces the amount of TFM required for effective treatment while minimizing the impact on non-target organisms.