The purpose of the present study was to investigate whether local prevention of luminal superoxide‐mediated biological damage in the rat jejunal mucosa could be achieved by use of cationized superoxide dismutase (SOD). Mucosal damage was induced in a closed circulating intestinal loop of the rat either by a mixture of xanthine and xanthine oxidase or by a mixture of xanthine, xanthine oxidase, and chelated ferrous sulfate. Thus, superoxide radicals or hydroxyl (OH·) radicals were induced. The mucosal activity of intracellular lactate dehydrogenase and the levels of cellular potassium ions were used to quantitatively characterize the tissue damage. SOD was cationized by reaction with N, N′‐dimethyl‐1, 3‐propanediamine to yield a soluble product or with polyhistidine to yield an insoluble product. The cationization yield and the activity of the modified enzymes were assessed, and the ability of the cationized enzymes to protect the rat jejunal mucosa against oxidative stress was studied. It was found that cationized SOD provided significant protection against mucosal damage induced by OH· radicals. The findings indicate the potential role of cationized enzymes in the local protection of the intestinal epithelium against pathological processes associated with oxidative stress.