Technical Abstract: Columnaris disease is one of the most important bacterial diseases of channel catfish, Ictalurus punctatus, commercially grown in the US. This disease can greatly diminish the profitability of aquaculture operations by large-scale mortality events, particularly in the fingerling production phase. Three experiments were conducted to evaluate the effects of pre-exposure of channel catfish fingerlings to copper sulfate (CuSO4) on susceptibility to columnaris disease. In experiment 1, fish were exposed for 24 h to 0 mg/L, 1 mg/L, 2 mg/L, or 4 mg/L CuSO4 and were challenged immediately with Flavobacterium columnare, the etiological agent of columnaris disease. The resulting survival data indicated that fish pre-exposed to CuSO4 exhibited significantly lowered survival compared to fish not exposed and then challenged. Experiment 2 was designed as above, except after the 24 h static exposure to CuSO4, an additional 24 h in flow-through water was allowed prior to challenge with F. columnare. In contrast to experiment 1, fish pre-exposed to CuSO4 and allowed an additional 24 h in flow-through water had a significantly higher survival rate than fish not exposed and then challenged. Experiment 3 evaluated the longevity of resistance to columnaris disease that was afforded by the pre-exposure to CuSO4; this experiment was conducted on the remaining, unused fish from experiment 2, but the challenge was 9 d after exposure to CuSO4. The increased survival rate of fish pre-exposed to CuSO4 was still significantly different, indicating the incurred resistance to F. columnare lasts at least a week after exposure to CuSO4.