This study investigated the effects of diets containing 0% or 20% DDGS, with or without enzyme supplementation, on broiler chickens subjected to a necrotic enteritis challenge. Key results showed that chickens fed DDGS and subjected to the challenge had poorer growth performance and higher caecal Clostridium perfringens counts. Serum IgA and IgM levels were also lower in challenged birds fed DDGS diets. Enzyme supplementation helped maintain feed intake and weight gain for challenged birds on DDGS diets without significantly affecting gut microflora or immune response. High DDGS inclusion may increase susceptibility to necrotic enteritis by allowing greater C. perfringens proliferation.