Although prednisolone treatment is effective in Cronkhite-Canada syndrome (CCS), its mechanisms of action are poorly understood. We performed analyses of cytokine expression and fecal microbiota in a patient with the concurrent occurrence of CCS and rectal cancer, in whom regression of polyposis was achieved by prednisolone. Regression of CCS polyps was accompanied by downregulation of proinflammatory cytokine expression and alterations in microbiota composition; a decrease in Bacteroides fragilis and Peptostreptococcus anaerobius with the promotion of inflammation. We could not completely exclude the possibility that alterations in fecal microbiota composition might be influenced by the presence of advanced cancer. However, this case suggests that the administration of PSL might lead to the regression of CCS polyps through alterations in gut microbiota composition and suppression of proinflammatory cytokine responses.