Acute toxicity tests were conducted for 96 h with larval Colorado squawfish (Ptychocheilus lucius) and razorback sucker (Xyrauchen texanus) in a reconstituted water quality simulating the San Juan River near Shiprock, New Mexico, to determine biological effect concentrations. Tests were conducted with arsenate, copper, selenate, selenite, zinc, and five mixtures of seven to nine inorganics simulating environmental mixtures reported for sites along the San Juan River (Ojo Amarillo Canyon, Gallegos Canyon, Hogback East Drain, Mancos River, and McElmo Creek). Razorback suckers were significantly more sensitive to arsenate, selenate, selenite, Hogback East Drain mixture, and Ojo Amarillo Canyon mixture than were Colorado squawfish. For both species, the Gallegos Canyon mixture had synergistic toxicity, the Mancos River and McElmo Creek mixtures had additive toxicity, and the Ojo Amarillo Canyon mixture had antagonistic toxicity. The Hogback East Drain mixture had additive toxicity to Colorado squawfish, but synergistic toxicity to razorback suckers. The major toxic component in the five mixtures was copper. Comparison of biological effect concentrations (i.e., 96-h LC₅₀) with environmental water concentrations from the San Juan River resulted in a ratio of <100, which revealed a high potential hazard for copper and all five environmental mixtures. The high hazard ratios suggest inorganic contaminants could adversely affect larval Colorado squawfish and razorback suckers in the San Juan River at sites receiving elevated inorganics such as from nonpoint discharges and irrigation return flows.