Recombinant human interleukin (IL)-11 is a multifunctional cytokine with hematopoietic, immunomodulatory, and epithelial cell protective activities. IL-11alpha receptors are expressed on the luminal surface of intestinal epithelial cells. It was hypothesized that orally administered IL-11 would prevent mucosal damage and protect against microbial invasion in a neutropenic rat model of gram-negative sepsis. IL-11 was administered daily by enteric, coated multiparticle pellets over the course of chemotherapy-induced neutropenia. Compared with the placebo group, IL-11-treated rats retained mucosal mass and had prolonged survival time, reduced pathologic changes, and reduced systemic levels of bacterial endotoxin and concentrations of Pseudomonas aeruginosa in target tissues. Enterocyte messenger RNA levels for tumor necrosis factor-alpha and interferon-gamma revealed that oral IL-11 reduced but did not prevent increased expression of these cytokine genes. These results indicate that orally administered IL-11 may preserve epithelial cell integrity in the presence of cytoreductive chemotherapy. This may represent a new treatment strategy for the prevention of infection in neutropenic hosts.