Secondary bacterial respiratory infections are a major cause of mortality in fall-weaned feedlot calves, and epidemiological studies implicate a variety of stressors as significant contributing factors. Experimental studies have identified stressors that may compromise pulmonary defense mechanisms but there is no evidence that these functional changes alter respiratory disease outcome. We used a model of combined viral and bacterial respiratory disease to determine if nutritional and psychological stressors (abrupt weaning; AW) altered respiratory disease mortality. Mortality was doubled in AW calves challenged with Mannheimia haemolytica four days after a primary bovine herpesvirus-1 (BHV-1) respiratory infection, when compared to calves adapted to weaning (pre-conditioned; PC) for two weeks prior to respiratory challenge. Reduced survival time and decreased lung pathology in the AW group suggested death was due to an acute systemic reaction. Viral shedding did not differ significantly between the two treatment groups. AW calves and all calves developing fatal pneumonia had significantly elevated interferon (IFN)-y levels in nasal secretions and increased systemic proinflammatory responses. Analysis of blood leukocytes revealed significantly increased CD14 and TLR4 gene expression in animals with fatal pneumonia. These analyses support the conclusion that stress enhanced innate immune responses to viral infection without altering the level of BHV-1 infection. These studies provide the first quantitative evidence that stress associated with abrupt weaning contributes significantly to fatal bovine respiratory disease.