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RATIONALE "Non-infectious" pulmonary complications are significant causes of morbidity and mortality post allogeneic hematopoietic cell transplant. Early onset viral reactivations or infections are common after transplant. Whether the first onset viral infection causes "non-infectious" pulmonary complications is unknown. OBJECTIVES To determine whether the first onset viral infection within 100 days post-transplant predisposes to development of "non-infectious" pulmonary complications. METHODS We performed a retrospective review of 738 allogeneic hematopoietic cell transplant patients enrolled from 2005 to 2011. We also established a novel bone marrow transplantation mouse model to test if herpesviral reactivation after transplant causes organ injury. MEASUREMENTS AND MAIN RESULTS First onset viral infections with human herpesvirus 6 or Epstein-Barr virus (EBV) within 100 days post-transplant increase the risk of developing idiopathic pneumonia syndrome (adjusted hazard ratio [aHR], 5.52; 95% CI, 1.61-18.96; P = 0.007; and aHR, 9.21; 95% CI, 2.63-32.18; P = 0.001, respectively). First infection with human cytomegalovirus increases risk of bronchiolitis obliterans syndrome (aHR, 2.88; 95% CI, 1.50-5.55; P = 0.002) and grade II to IV acute graft-versus-host disease (aHR, 1.59; 95% CI, 1.06-2.39; P = 0.02). Murine roseolovirus, a homolog of human herpesvirus 6, can also be reactivated in the lung and other organs after bone marrow transplantation. Reactivation of murine roseolovirus induced an idiopathic pneumonia syndrome-like phenotype and aggravated acute graft-versus-host disease. CONCLUSIONS First onset herpesviral infection within 100 days post allogeneic hematopoietic cell transplant increases risk of pulmonary complications. Experimentally reactivating murine roseolovirus causes organ injury similar to phenotypes seen in human transplant recipients.