Aims: The aim of the study was to evaluate the efficacy of probiotics on gut-derived sepsis caused by Pseudomonas aeruginosa in immunocompromised mice. Methods and Results: After oral inoculation of P. aeruginosa, mice were treated with cyclophosphamide to induce leucopenia and translocation of the intestinal P. aeruginosa into blood, thereby producing gut-derived sepsis. In this model, administration of 1 x 10(9) CFU of Bifidobacterium longum strain BB536 for 10 days significantly (P < 0.01) increased the survival rate compared with groups of mice administered either with Bifidobacterium breve strain ATCC 15700 or excipients contained in the probiotic bacterial powder. Administration of B. longum significantly decreased viable counts of P. aeruginosa in the liver and blood compared with other groups. Culture of intestinal contents revealed a significantly lower viable count of P. aeruginosa in the jejunum of B. longum-treated mice compared with other groups of mice. Furthermore, in vitro data demonstrated that B. longum possessed apparently higher adherent activity to Caco-2 cell monolayers and significantly suppressed the adherence of P. aeruginosa to the monolayers of cells compared with other groups. Conclusion: Oral administration of B. longum protects mice against gut-derived sepsis caused by P. aeruginosa, and the effect may be due to interference of P. aeruginosa adherence to intestinal epithelial cells. Significance and Impact of this Study: This study demonstrated that oral administration of B. longum BB536 is effective to protect against opportunistic infection with drug-resistant bacteria such as P. aeruginosa. The results suggest that probiotics may play an important role even in the immunocompromised patients.