AbstractCopper sulfate (CuSO4) and potassium permanganate (KMnO4) were evaluated for their effectiveness to curtail mortality and decrease bacterial load in fish tissues and water in channel catfish Ictalurus punctatus infected with Flavobacterium columnare, the causative agent of columnaris. Fish (average size, 16.6 g and 13.7 cm) were obtained from a single culture tank undergoing an epizootic of columnaris and were stocked at a density of 30 fish per tank in each of 12 tanks. The study consisted of three treatments (n = 4 replicates per treatment): an untreated control group, a CuSO4‐treated group, and a KMnO4‐treated group. Treatment rates were 2.1 mg/L CuSO4 and 3.0 mg/L KMnO4 and were applied on three consecutive days at 24‐h intervals. Caudal fin, gill, and liver samples were taken from one fish of each replication 24 h after the last treatment for analysis by quantitative real time PCR. A significant improvement in survival was noted among fish treated with CuSO4 (72.7%) compared with the control fish (38.5%) and the KMnO4‐treated fish (52.2%). Survival of the KMnO4‐treated fish was not significantly different from the control. Quantitative PCR indicated a significant reduction of bacteria in the water after the first and second treatments of both therapeutants; no difference was detected in fish tissues. Histological analysis of gill samples 24 h after the last treatment indicated that CuSO4‐treated fish exhibited significantly less gill damage than untreated controls and there was no difference in KMnO4‐treated fish. Copper sulfate therapy significantly improved survival, reduced the number of bacteria in the water, and reduced gill pathologies associated with F. columnare infection in channel catfish.