Rationale: There are no reports of the systemic human pathology of the novel swine H1N1 influenza (S-OIV) infection. Objectives: The autopsy findings of 21 Brazilian patients with confirmed S-OIV infection are presented. These patients died in the winter of the southern hemisphere 2009 pandemic, with acute respiratory failure. Methods: Lung tissue was submitted to virologic and bacteriologic analysis with rRT-PCR and electron microscopy. Expression of Toll-like receptor (TLR)-3, interferon-, TNF-, CD8+T cells and granzyme B+ cells in the lungs was investigated by immunohistochemistry. Results: Patients were aged from one to 68 years (72% between 30 and 59 years), and 12 were male. Sixteen patients had preexisting medical conditions. Diffuse alveolar damage (DAD) was present in 20 individuals. In six patients, DAD was associated with necrotizing bronchiolitis and in 5 with extensive hemorrhage. There was also a cytopathic effect in the bronchial and alveolar epithelial cells, as well as necrosis, epithelial hyperplasia and squamous metaplasia of the large airways. There was marked expression of TLR-3 and IFN- and a large number of CD8+ T cells and granzyme B+ cells within the lung tissue. Changes in other organs were mainly secondary to multiple organ failure. Conclusions: Autopsies have shown that the main pathological changes associated with S-OIV infection are localized to the lungs, where three distinct histological patterns can be identified. We also show evidence of ongoing pulmonary aberrant immune response. Our results reinforce the utility of autopsy in increasing the understanding of the novel human influenza A (H1N1) infection.