The 1918 influenza virus caused severe respiratory disease in cynomolgus macaques, leading to acute respiratory distress and death. Infected animals exhibited an aberrant innate immune response, characterized by dysregulated antiviral defenses, which failed to protect against the virus. This study demonstrates that the 1918 virus is highly pathogenic in primates, similar to its virulence in mice. The virus replicated extensively in respiratory tissues and was detected in the heart and spleen of some animals. In contrast, the conventional human virus K173 showed milder symptoms and lower replication levels. The 1918 virus caused severe lung damage, with extensive alveolar damage and viral antigen expression, while K173-infected animals showed signs of healing by day 8. The 1918 virus induced a more pronounced immune response, with elevated levels of cytokines such as IL-6, IL-8, CCL2, and CCL5. The global gene expression profiles of 1918-virus-infected animals showed sustained immune responses, unlike those of K173-infected animals, which exhibited a more dynamic response. The 1918 virus induced a different antiviral response compared to K173, with reduced sensitivity to type I interferon responses. The study highlights the importance of understanding the virus-host interaction to develop interventions that can counteract the virus's ability to modulate host immune responses, which may be critical in severe infections caused by viruses such as H5N1. The results suggest that atypical innate immune responses may contribute to the severity and outcome of 1918 virus infection. The study was conducted in a biosafety level 4 facility, with all procedures approved by the Canadian Council on Animal Care. The research was supported by various funding sources, including the Public Health Agency of Canada and grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. The microarray data were deposited in ArrayExpress with accession number E-TABM-181.The 1918 influenza virus caused severe respiratory disease in cynomolgus macaques, leading to acute respiratory distress and death. Infected animals exhibited an aberrant innate immune response, characterized by dysregulated antiviral defenses, which failed to protect against the virus. This study demonstrates that the 1918 virus is highly pathogenic in primates, similar to its virulence in mice. The virus replicated extensively in respiratory tissues and was detected in the heart and spleen of some animals. In contrast, the conventional human virus K173 showed milder symptoms and lower replication levels. The 1918 virus caused severe lung damage, with extensive alveolar damage and viral antigen expression, while K173-infected animals showed signs of healing by day 8. The 1918 virus induced a more pronounced immune response, with elevated levels of cytokines such as IL-6, IL-8, CCL2, and CCL5. The global gene expression profiles of 1918-virus-infected animals showed sustained immune responses, unlike those of K173-infected animals, which exhibited a more dynamic response. The 1918 virus induced a different antiviral response compared to K173, with reduced sensitivity to type I interferon responses. The study highlights the importance of understanding the virus-host interaction to develop interventions that can counteract the virus's ability to modulate host immune responses, which may be critical in severe infections caused by viruses such as H5N1. The results suggest that atypical innate immune responses may contribute to the severity and outcome of 1918 virus infection. The study was conducted in a biosafety level 4 facility, with all procedures approved by the Canadian Council on Animal Care. The research was supported by various funding sources, including the Public Health Agency of Canada and grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. The microarray data were deposited in ArrayExpress with accession number E-TABM-181.