Background: Neutron irradiation (IR) has been proven to cause more serious damage than gamma IR. Preventing and curing neutron IR damage remains an urgent issue. Aims: The objective of this study was to investigate the radioprotective effects of IL-11 against neutron IR-induced damage in small intestine of mice. Methods: Mice were exposed to 3-Gy neutron IR whole body and then treated with 500 μg/kg interleukin-11 (IL-11) intraperitoneally every day. Mice were observed at various time-points over 1-5 days after IR. IEC-6 cells were exposed to 4 Gy neutron IR, and 100 ng/mL rhIL-11 was added to culture medium. Cell proliferation activity was estimated by MTT assay and rates of apoptosis were estimated by flow cytometry. Results: IL-11 slightly alleviated the incidence of diarrhea in the mice and promoted intestinal epithelia regeneration. In the in vitro study, neutron IR activated extracellular signal-regulated kinase (ERK)1/2 phosphorylation in intestinal epithelial cells constitutively, which was initially suppressed and then activated later by IL-11. The MEK-specific inhibitor U0126 could antagonize the positive effect of IL-11 on cell growth. Phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation was suppressed after neutron IR, but could be triggered by IL-11 to protect the cells. The PI3K inhibitor LY294002 suppressed the positive effect of IL-11 on cell growth, and antagonized the protective effect of IL-11 against cell death after neutron IR. Conclusion: IL-11 increases cell proliferation after neutron IR in MEK and PI3K-dependent signaling pathways, but protects cells against death only in the PI3K-dependent signaling pathway. © 2014 Springer Science+Business Media.