We hypothesized that IL-11 would protect against radiation-induced thoracic injury. To test this hypothesis, we compared the survival of rIL-11 and vehicle-treated control mice after 25 Gy of thoracic irradiation, and initiated studies to elucidate the mechanism of the observed protection. This dose of radiation killed 50% of the control mice during the first 2 wk after irradiation. In contrast, the s.c. administration of rIL-11 resulted in significant radioprotection with 89% of the rIL-11-treated animals surviving the study interval (p < 0.001). This radioprotection was at least partially specific for normal thoracic structures since rIL-11 did not alter the development or radiosensitivity of EMT6 tumor cells growing as lung metastases. TNF mRNA was not detected in normal lungs but was impressively induced after thoracic irradiation. Treatment with rIL-11 abrogated this increase. Parallel in vitro studies demonstrated that rIL-11 inhibits LPS and radiation-induced macrophage TNF protein production and mRNA accumulation. These studies demonstrate that rIL-11 reduces the mortality following thoracic irradiation, without enhancing the development or diminishing the radiosensitivity of pulmonary metastatic tumors. They also demonstrate that rIL-11 inhibits both radiation-induced TNF mRNA expression in vivo and macrophage TNF protein production and mRNA accumulation in vitro, suggesting that the radioprotective effects of rIL-11 may be mediated, at least in part, via the modulation of TNF production.