Technical Abstract: A histological study was done to evaluate the effect of waterborne exposures of copper sulfate (CuSO4) on channel catfish (Ictalurus punctatus). Channel catfish were exposed daily for 11 consecutive days to three concentrations of CuSO4 representing one, three and five times the recommended therapeutic level based on the total alkalinity. Fish were treated with CuSO4 in flow-through tanks at a flow rate of 0.633 L/min. More than half the copper (Cu) was flushed in 1 h which is similar to the elimination rates in ponds (due to the rapid uptake of Cu by aquatic plants or algae and the binding to organic and inorganic material). All fish were clinically normal and no fish died during the experiment. All examined tissues were grossly and histologically normal as well. The absence of histological lesions was attributed to the brief daily exposure to copper and the moderate total alkalinity and the total hardness of the well water used. The results of this study suggest that the use of CuSO4 is safe provided that the treatment applied is considered in relation to the total alkalinity of the water. The present study followed a protocol developed in cooperation with the U.S. Food and Drug Administration (FDA), Center for Veterinary Medicine and designed to support the data package required for the approval of CuSO4 as an aquaculture therapeutant.