Objective To compare the histopathological changes of large intestinal mucosa between a rat ulcerative colitis (UC) model induced by dextran sulfate sodium (DSS) and human UC, and examine the pathological mechanisms. Methods Twenty healthy Sprague Dawley male rats (specific?pathogen?free grade)were divided into normal control and model (free access to 5% DSS solution) groups (n =10 per group). The general condition, appearance of the large intestine, and histopathological changes of the mucosa in rats were compared with nine cases of human UC admitted in our hospital. Results The most common lesions involved large intestinal cryptitis, crypt abscesses, crypt atrophy and structural disorder, and erosion and ulcer formation in the rat and human UC cases. In the majority of rats, early lesions showed atrophy of ~1/3 of crypts in the inferior lamina propria, which gradually developed to the entire layer. Interstitial inflammation predominantly involved macrophages, with no plasma cells. The surface epithelia then degenerated, with necrosis and shedding, and formation of a mucosal ulcer, followed by multiple intravascular thrombosis, individual thrombus organization, and occasional glandular dysplasia. By contrast, early stage human UC typically involved acute inflammation of surface epithelia and the upper 1/3 of crypts, while glandular destruction and atrophy were associated with crypt abscesses. All of the human cases were accompanied by basic pathological changes involving chronic enteritis and atypical gland hyperplasia, and occasional thrombosis with/ without organization. Conclusions The common pathogenesis of UC in human ulcerative colitis and DSS?induced rat UC involves injury of large intestinal crypt stem cells. However, DSS?treated rats showed initial lower 1/3 crypt damage expanding into whole crypt destruction, with secondary inflammation, while human UC showed the opposite pattern. These differences should be considered when using this model to study the efficacy and mechanism of drugs for treatment of Ulcerative colitis.