A study was conducted to examine the effect of dietary levels of distiller’s dried grains with solubles (DDGS) on growth, body composition, hematology, immune response, and resistance of channel catfish, Ictalurus punctatus, to Edwardsiella ictaluri challenge. Five diets containing 0, 10, 20, 30, and 40% DDGS with supplemental lysine (Diets 1–5) as partial replacements of a combination of soybean meal and cornmeal on an equal protein basis were fed to juvenile catfish (13.33 ± 0.25 g) for 12 wk. Growth performance and feed utilization efficiency were similar for fish in all treatments. Body lipid and moisture increased and decreased, respectively, in fish feed DDGS-containing diets relative to the control group. Dietary treatment had no effect on red and white blood cell counts. Hemoglobin and hematocrit were significantly higher in fish fed diets containing DDGS than in those fed the control diet. Fish fed 20–40% DDGS diets had increased serum total immunoglobulin, and those fed the 30% DDGS diet had significantly increased antibody titers 21 d following E. ictaluri challenge. Other immune variables evaluated were not affected by dietary treatments. Preliminary results on bacterial challenge showed an increased resistance against E. ictaluri in fish fed DDGS-containing diets (Diets 2–5).