Therapy-induced inflammation and progressive fibrosis limit the efficacy of thoracic radiotherapy for lung neoplasms. However, mice bearing a null mutation of intercellular adhesion molecule 1 (ICAM-1) have previously been found to display no inflammatory cell infiltration into the lung following thoracic irradiation. We investigated the role of ICAM-1-mediated inflammation in the pathogenesis of radiation-induced pulmonary fibrosis in mice with a homozygous null mutation in the ICAM-1 gene (ICAM-1(-/-)) and in wild-type mice (ICAM-1(+/+)).Groups of 10 mice were each irradiated with total doses of 12.5, 14, 16, 17, or 18 Gy to the thorax or were mock irradiated. Inflammatory cell infiltration was measured by immunohistochemical staining of lung sections for leukocyte-common antigen (LCA). Dynamic pulmonary compliance was determined by plethysmography. Pulmonary fibrosis was evaluated by measuring alveolar septal wall thickness and the hydroxyproline content of lungs by immunohistochemical staining of lung sections for collagen III and by Masson's trichrome staining of lung sections. All statistical tests were two-sided.Lungs of irradiated ICAM-1(-/-) mice had statistically significantly fewer LCA-positive cells than the lungs of irradiated ICAM-1(+/+) mice at all radiation doses (P<.001). ICAM-1(-/-) mice had a higher mean dynamic pulmonary compliance than ICAM-1(+/+) mice following irradiation. The incidence of respiratory insufficiency 18 months after thoracic irradiation was statistically significantly lower in ICAM-1(-/-) mice than in ICAM-1(+/+) mice (odds ratio = 0.19 [95% confidence interval = 0.06 to 0.58], overall P =.0036). ICAM-1(-/-) mice had less pulmonary fibrosis and reduced thickening of the alveolar septum following thoracic irradiation than did ICAM-1(+/+) mice. The lungs of irradiated ICAM-1(-/-) mice had less hydroxyproline than did the lungs of irradiated ICAM-1(+/+) mice (P =.04).ICAM-1 and inflammation contribute to pulmonary fibrosis and impaired pulmonary compliance following thoracic irradiation. Agents that block ICAM-1 function or expression should be studied for their effects on the prevention of radiation-induced pulmonary fibrosis.