The effect of exogenous mixed-enzyme supplementation (xylanase, β-glucanase, and pectinase) and coccidia vaccine challenge (CVC, Coccivac B-52™) on broilers fed a corn-SBM (CS) and a wheat-CS (WCS)-based diet was examined in this study. On day 14, 448 Cobb by-product breeder male broiler chickens were assigned to treatments (factorial arrangement) in a completely randomized design, with each treatment replicated seven times. Treatment effect was evaluated within each diet type as a 2 (enzyme levels) x 2 (CVC, 0 or 20X) factorial arrangement of treatments 7 and 14 days post-CVC. The 7-day (days 14-21) post-CVC, BWG, and feed efficiency (birds on the CS-based diet) were lower (