Diisocyanates are well-recognized to cause occupational asthma, yet diisocyanate asthma can be challenging to diagnose and differentiate from asthma induced by other allergens. The present study assesses the potential contribution of methylene diphenyl diisocyanate (MDI) to a workplace fatality. Examination of medical records, tissue, and blood from the deceased worker were undertaken. Formalin-fixed paraffin-embedded lung tissue sections were assessed through histologic and immunochemical stains. Serum MDI-specific IgE and IgG, and total IgE, were measured by enzyme-linked immunosorbent assays and/or Western blot. Information about potential chemical exposures and industrial processes in the workplace were provided by the employer and through interviews with co-workers. Review of the worker's medical records, occupational history, and autopsy findings were consistent with severe asthma as the cause of death, and ruled out cardiac disease, pulmonary embolism, or stroke. Lung pathology revealed hallmarks of asthma including smooth muscle hypertrophy, eosinophilia, basement membrane thickening, and mucus plugging of bronchioles. Immunochemical staining for MDI was positive in the thickened basement membrane of inflamed airways. MDI-specific serum IgE and IgG were significantly elevated and demonstrated specificity for MDI versus other diisocyanates, however, total serum IgE was normal (24 IU/ml). The workplace had recently introduced MDI into the foundry as part of a new process, but MDI air levels had not been measured. Respirators were not required. In summary, post-mortem findings support the diagnosis of diisocyanate asthma and a severe asthma attack at work as the cause of death in a foundry worker.