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Juvenile channel catfish were fed for 12 wk with diets containing wheat distiller's dried grains with solubles (WDDGS) at levels of 0 (diet 1), 10, 20, 30, and 40% without lysine supplementation (diets 2–5) or with lysine supplementation (diets 6–9) as substitutes of soybean and corn meal mixture. Fish fed diet 5 had the lowest weight gain (WG), feed efficiency ratio (FER), protein efficiency ratio (PER), feed intake (FI), and survival. Fish fed diets 7–9 had significantly higher WG, FER, and PER than fish fed diet 1. Body protein decreased in fish fed diets 4 and 5, while body lipid tended to increase in fish fed WDDGS-containing diets. Fish fed diet 5 developed anemia. The number of days to first mortality was delayed and cumulative mortality 21-d post-challenge with Edwardsiella ictaluri was lower in fish fed WDDGS-containing diets relative to fish fed diet 1. Further decrease in mortality was obtained in fish fed diets with 20–40% WDDGS, regardless of lysine supplementation. Serum protein, immunoglobulin, and lysozyme were unaffected by dietary treatments. Serum complement and antibody titer against E. ictaluri significantly differed among treatments but did not appear to be related to cumulative mortality following experimental challenge.